Special Feature
The DHEA Controversy
By Dónal P. O’Mathúna, PhD
The subtitles of recent popular dehydro-epiandrosterone (DHEA) books tell it all: Unlocking the Secrets to the Fountain of Youth,1 Exploring the Link Between Youth & Aging,2 and The Natural Hormone That Helps Fight Disease, Improves Mood & Energy, Boosts Your Sex Drive, and Influences Longevity.3 However, the authors of cited clinical research studies report, "The hype is out of control DHEA is the snake oil of the ’90s. DHEA sales could be a disaster in the making."4 How can a busy physician make sense of these contradictory claims?
Introduction and Claims
In 1996, the scientist who first isolated the sulfate ester of DHEA (DHEAS) concluded: "Several years will be necessary to pass from precise and limited observation to a sure, efficacious product useable by many people."5
DHEA is supposed to slow aging, burn fat, build muscle mass, strengthen the immune system, treat lupus, and help prevent heart disease, cancer, diabetes, and Alzheimer’s and Parkinson’s diseases.6 It is also reported to boost libido, alleviate depression, and increase general feelings of strength, stamina, and well-being.7 It is most commonly self-prescribed as an antidote to the general effects of aging, especially around menopause.6
From 1985 to 1994, DHEA was available only by prescription. The 1994 Dietary Supplement Health and Education Act reclassified DHEA as a dietary supplement, allowing it to be sold over-the-counter.
Pharmacology
DHEA is a steroid hormone, closely related to testosterone and estrogen. DHEA is converted endogenously into DHEAS, the predominant form in the circulation.5 If taken orally, DHEAS is converted into DHEA in the stomach. Endogenous DHEA is made from cholesterol in the adrenal glands. Fetuses produce copious amounts, but levels drop precipitously at birth, increase again around age six or seven, peak in the mid-20s, and then gradually decline.8 At its peak, DHEA is the most abundant hormone in the circulation. By the time people are in their 60s, the levels have dropped to 10-20% of their peak values. DHEA levels are lowered by some illnesses, including rheumatoid arthritis and major depressive disorders, and by periods of stress.9 Levels are increased by smoking and alcohol.10
Decreased DHEA levels are accompanied by reduced levels of other steroids, including testosterone and androstenedione.11 The steroid level that correlates best with chronological age and age-related cognitive and physical deficits is bioavailable testosterone (BT).11 Most testosterone in the body is tightly bound to globulins, but a small proportion of BT is loosely bound to albumin, making it readily available for use by tissues.12
DHEA may play a role in binding albumin molecules, changing their shape, and giving them more affinity for testosterone, thus decreasing the levels of BT.12 This effect is dose dependent. Administration of moderate amounts of DHEA restored serum DHEA to youthful levels, but did not affect BT levels.13 High levels of oral DHEA reduced BT levels.12 Intramuscular administration of testosterone along with moderate doses of DHEA may restore both BT and DHEA to peak levels.
Clinical Studies
The vast majority of research on DHEA supplements has been conducted on animals. The studies have shown positive effects in preventing cancer, diabetes, heart disease, viral infections, and brain diseases. The relevance for humans is questionable since only humans and a few primates synthesize and secrete DHEA and DHEAS.10 A 1998 review found 23 clinical investigations of DHEA supplementation since 1966.10 Many of these studies were unblinded with no control groups. One had 28 subjects, but the others had fewer than 15. Different preparations, doses, and routes of administration were used. The reviewers concluded, "The clinical literature is fraught with problems."10
Differences between men’s and women’s responses have been noted.14 A 10% DHEA cream was evaluated in 14 women aged 60-70 years, 10 of whom began with completely atrophic vaginal smears.15 After therapy, eight had vaginal cytology typical of menstruating women, four showed "improvement," and two showed no significant changes. Hip bone mineral density also increased significantly (P < 0.05). Eighty percent of the subjects reported an improved sense of well-being, confirming earlier findings.13
A study with 22 post-menopausal women studied the effect of DHEAS on serum beta-endorphin levels.16 Post-menopausal beta-endorphin levels are reduced, and raising them was assumed to correlate with an improved sense of well-being. The subjects were randomly divided into three groups, one receiving oral DHEAS (n = 8; 50 mg/d), the second (n = 8) receiving oral DHEAS (50 mg/d) plus transdermal estradiol (50 µg/patch), and the third receiving transdermal estradiol alone (n = 6; 50 µg/patch). All three therapies showed equivalent restoration of beta-endorphin levels, and the authors concluded this supported the therapeutic efficacy of DHEAS for improving one’s sense of well-being.
The first double-blind, placebo-controlled trial of DHEA for major depression was recently reported.17 Twenty-two patients with major depression were randomly assigned to DHEA (maximum, 90 mg/d) or placebo (n = 11 in each group). Five of those taking DHEA and none of those taking placebo showed at least a 50% reduction in depressive symptoms.
Formulation and Dosage
Oral administration of 25-50 mg DHEA daily returns most people’s DHEA levels to their youthful peaks.5 But optimal dosages are difficult to determine for numerous reasons. Healthy people of similar age have DHEAS blood levels that vary more than threefold, and no correlation exists between these levels and overall health or life expectancy.5 Dosage determinations are also complicated by conditions causing DHEA levels to fluctuate (some are listed under "Pharmacology").
DHEA is often sold in precursor form, usually as plant extracts (wild yams and soy), with accompanying claims that the plant steroids are converted into DHEA. Humans have no metabolic pathway to accomplish this long, complex synthesis, making it unlikely these products affect blood DHEA levels.8 Lack of regulation is another problem. One review found commercial products contained 0-150% of the labeled amount.18 Nine of the 16 products failed to meet standard pharmaceutical specifications of 90-110% of labeled amount.
Adverse Effects
Some women taking DHEA stop menstruating, grow body and facial hair, and develop deeper voices.7 DHEA has been reported to decrease HDL cholesterol levels in women, though not in men.14
The association between DHEA and breast cancer risk is complex. A study with 213 women not taking DHEA supplements (mean age, 62 years) found postmenopausal women with elevated levels of endogenous estradiol, testosterone, and DHEA had an increased risk of breast cancer.19 However, when the results for all three hormones were analyzed together, the influence of DHEA was reduced by 83%.
In men, an increased testosterone level could enlarge the prostate, interfering with urination, or stimulate growth of prostate cancer, although reports of this were not found.7 A recent study found no changes in the prostate or in PSA levels.16 At low concentrations, DHEA protected in vitro liver cells against lipid peroxidation, but at slightly higher concentrations it promoted oxidation.20
Conclusion
DHEA is a natural steroid hormone but its natural function remains unclear. Its role in human metabolism is widespread, but poorly understood. It is not a typical hormone because its receptor has not yet been found (if it has one). Its effect may have more to do with its metabolites than its native form. It is widely involved in human metabolism, but precisely how is poorly understood. Its efficacy and long-term safety in treating age-related medical problems remain unclear, although recent evidence suggests promise in diseases of hormonal regulation.
Recommendation
It is premature to recommend using DHEA supplements for relief of menopausal symptoms, though short-term use does seem to improve people’s sense of well-being. Since DHEA is associated with many divergent metabolic processes, the chances for adverse effects are high. However, DHEA is the subject of active clinical investigation and some results are encouraging. Until the results of larger, long-term studies are available, DHEA supplementation cannot be recommended as an evidence-based therapeutic option in menopause. (Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mt. Carmel College of Nursing, Columbus, OH.)
References
1. Ley BM. DHEA: Unlocking the Secrets to the Fountain of Youth. Aliso Viejo, CA: BL Publications; 1996.
2. Pascal A. DHEA: The Fountain of Youth Discovered? Exploring the Link Between Youth & Aging. Malibu, CA: Van der Kar Press; 1996.
3. Sahelian R. DHEA: A Practical Guide: The Natural Hormone That . . . Garden City Park, NY: Avery, 1996.
4. Skerret PJ. DHEA: Ignore the hype. HealthNews 1996. Available at http://www.healthnet.ivi.com.
5. Baulieu EE. Dehydroepiandrosterone (DHEA): A fountain of youth? J Clin Endocrinol Metab 1996;81: 3147-3151.
6. Skolnick AA. Scientific verdict still out on DHEA. JAMA 1996;276:1365-1367.
7. Dehydroepiandrosterone (DHEA). Med Lett Drugs Ther 1996;38:91-92.
8. DHEA: Unraveling the mystery. University of California. Berkeley Wellness Lett 1999;15(2):1-2.
9. Herbert J. The age of dehydroepiandrosterone. Lancet 1995;345:1193-1194.
10. Katz S, Morales AJ. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DS) as therapeutic options in menopause. Semin Reprod Endocrinol 1998;16: 161-170.
11. Morley JE, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: Progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA 1997;94:7537-7542.
12. Roberts E. The importance of being dehydroepiandrosterone sulfate (in the blood of primates): A longer and healthier life? Biochem Pharmacol 1999;57:329-346.
13. Morales AJ, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994;78:1360-1367.
14. Morales AJ, et al. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 1998;49:421-432.
15. Labrie F, et al. Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab 1997;82:3498-3505.
16. Stomati M, et al. Endocrine, neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women. Gynecol Endocrinol 1999;13:15-25.
17. Wolkowitz OM, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999;156:646-649.
18. Parasrampuria J, et al. Quality control of dehydroepiandrosterone dietary supplement products. JAMA 1998;280:1565.
19. Dorgan JF, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999;91:380-381.
20. Gallo M, et al. Protective effect of dehydroepiandrosterone against lipid peroxidation in a human liver cell line. Eur J Endocrinol 1999;141:35-39.
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