DHEA Not Recommended in Treatment of HIV Infection
May 1998; Volume 1: 56-58
By E.P. Barrette, MD
In spite of the recent successes of the new anti-retroviral medications, many HIV-positive patients continue to use alternative medicines. Some remain distrustful of conventional medicines, particularly AZT, while others use supplements to complement standard therapies. However, clinicans should be ready to argue strongly when an alternative therapy either offers no benefit or is shown to cause harm.
DHEA (dehydroepiandrosterone) continues to remain popular among HIV-positive individuals primarily as a treatment for wasting. However, some advocates also describe immune benefits, increased energy, improved mood, and an improved overall sense of well-being. Although some early preliminary studies suggested a role in the treatment of HIV infection, no published clinical trials of DHEA in HIV infection support its use. Before the U.S. Dietary Supplement Health and Education Act made it available again, sales of DHEA over-the-counter had been banned by the FDA.
History
In the 1950s, DHEA and its sulfated form, DHEAS, were recognized as the predominant steroids formed by the adrenal glands. Since that time, scientists have continued to study their physiologic role. In 1985, the promotion of DHEA use for "natural" weight reduction, prolonged longevity, and improved sexual enjoyment resulted in the FDA banning over-the-counter sales. The FDA felt that the safety of DHEA had not been evaluated, that DHEA was being promoted as a drug, and that controlled clinical trials were lacking. With the passage of the U.S. Dietary Supplement Health and Education Act in 1994, however, DHEA again became available.
Though it is promoted as a dietary supplement, its only natural source is primate adrenal glands. Though the 1994 act prohibits product labeling to include "drug intent," marketing of DHEA frequently mentions benefits such as weight control, reversal of the aging process, increased immune function, and increased muscle mass. Even prior to 1994, DHEA was readily available through AIDS buyers clubs. Though not approved by the FDA for medical uses, DHEA's popularity continues.
Mechanisms of Action
DHEA and DHEAS are the major steroid products of the adrenal glands in humans. More than 99% of DHEA is sulfated before secretion. The estimated half-life of DHEA and DHEAS are 15-30 minutes and 7-10 hours, respectively. The serum concentrations reflect the different clearance rates: DHEA 2-9 g/L (7-31 mmol/L), DHEAS 500-2500 ng/mL (1.0-6.7 mmol/L). Levels remain low after birth until age 7 when they begin to rise. Peak values are seen between ages 25 and 30. Afterward, levels decline 2% per year, leveling off at a value less than 20% of the peak by the eighth decade.1
Despite much research, the roles of DHEA and DHEAS remain incompletely understood. Both androgenic and estrogenic effects have been noted, and the relative predominance of one effect appears to depend on the background hormonal levels. Many of the end-organ effects may occur via peripheral conversion of DHEA and DHEAS to androgens and estrogens. For example, in older men DHEA may act via an estrogenic effect and confer some protection for cardiovascular disease, but in postmenopausal woman DHEA may exert an androgenic effect and increase the risk of cardiovascular disease.2 In primates, high levels of DHEA are also seen. However, in most laboratory animals (including rodents), DHEA and DHEAS levels are very low, leading one to question the extrapolation of most animal data to humans.
In HIV infection, adrenal gland involvement is commonly noted at a postmortem exam by cytomegalovirus, Mycobacterium avium complex, and other opportunistic pathogens. While the symptoms of adrenal insufficiency overlap with the symptoms of HIV itself, frank adrenal insufficiency is uncommon in HIV-infected individuals. Subnormal responses to synthetic ACTH stimulation tests, however, have been seen.
Clinical Studies
DHEA improves immune function in rodents, in part by increasing interleukin-2 production.
The popular press has described DHEA as the "fountain of youth" based primarily on one six-month trial.3 This double-blind crossover trial compared placebo vs. 50 mg of DHEA in 30 subjects, 40-70 years old. This dose resulted in serum levels of DHEA and DHEAS comparable to that of young adults. A total of 82% of the women and 67% of the men on DHEA described an improved sense of well-being at 12 weeks, compared to less than 10% taking placebo.
A brief report in 1989 correlated DHEA levels to HIV status in a small group of individuals: HIV-negative 8.0 mol/L, HIV-positive 5.8 mol/L, and AIDS 3.9 mol/L (n = 27.4) Shortly thereafter, two larger trials confirmed this trend. DHEA levels below 1.8 g/L were associated with more than double the risk of developing AIDS in two years (relative hazard = 2.34; P = 0.01) among 108 HIV-positive men with CD4 counts of 200-499.5
A similar case control in a prospectively followed cohort of homosexual men showed that HIV-positive men had lower DHEA levels than HIV-negative men.6 Among HIVpositive men, those who progressed to AIDS within five years had DHEA levels that had declined compared to men who had not progressed. Those who progressed sooner had lower DHEA levels at entry. DHEA levels below 2.02 g/L independently predicted progression to AIDS. Lower DHEAS levels in more advanced HIV infection has been seen in two other studies. Diminished DHEAS levels correlated with lower CD4 cell counts. However, in a study of HIV-infected men with hemophilia, declining DHEAS levels were associated with general health status and not specifically progression of HIV infection.
A series of in vitro experiments using DHEA in HIV infection demonstrated modest inhibition of HIV replication, inhibition of reactivation of HIV latency, and inhibition of AZT-resistant HIV infection.7 An open-label trial of high-dose DHEA (250, 500, and 750 mg tid) for 16 weeks in mildly symptomatic HIV-positive men with CD4 counts between 250 and 600 not receiving other antiretroviral medications showed no sustained improvement in CD4 counts, p24 antigenemia, or microglobulin levels.8 An uncontrolled trial reported as an abstract suggests that DHEA lowers viral load in patients with AIDS. One group has reported higher DHEA levels in HIV-positive men with Kaposi's sarcoma compared to HIV-positive men without Kaposi's sarcoma. Those patients with Kaposi's sarcoma who had received interferon and then entered a complete remission also had a marked decrease in their DHEA level.9
Adverse Effects
Androgenic side effects have been seen in women: hirsutism, acne, hair loss, deepening of the voice. Some of these effects may not be reversible. High doses have caused fatigue, headaches, and insomnia. Transient hepatitis has been reported. Androgens can promote the growth of prostate cancer. No clinical data regarding DHEA and prostate cancer have been reported. While some epidemiological studies suggest that low levels of DHEA are associated with breast cancer, one report found an association between higher levels of DHEA in women and ovarian cancer.10 In this prospective case-control study, stored serum samples from women who developed ovarian cancer had significantly higher levels of DHEA than controls, particularly in premenopausal women. Very high doses in rats cause liver cancer, exert estrogenic effects, result in fetal anomalies, and can act as an abortifacient.
Drug Interactions
No information is available.
Formulation
DHEA is readily available in 10, 25, and 50 mg doses. It is often combined with other vitamins and herbs.
Dosage
A dose of 25-50 mg is usually adequate to increase the serum level in an older individual to a value seen in a 20- to 30-year-old. Short-term trials have used much higher dosages.
Conclusion
Although there is evidence that DHEA levels decline as HIV infection progresses, no convincing evidence exists that shows benefit for either physiological replacement (25-50 mg) or higher pharmacological dosing in HIV infection. With the reported high levels of DHEA in men with Kaposi's sarcoma and the androgenic effects in women, HIV-positive patients should be cautioned against including DHEA with their supplements. Daily supplements of B complex, vitamins E and C, in addition to a multivitamin should be encouraged. Until more is known, the use of DHEA to treat HIV infection should not be recommended.
References
1. Baulieu EE. Dehydroepiandrosterone (DHEA): A fountain of youth? J Clin Endocrinol Metab 1996;81:3147-3151.
2. Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994;343:1479-1481.
3. Morales AJ, Nolan JJ, Nelson JC, et al. Effects of replacement dose of dehydroepiandrosterone in men and woman of advancing age. J Clin Endocrinol Metab 1994;78:1360-1367.
4. Merril CR, Harrington MG, Sunderland T. Plasma dehydroepiandrosterone levels in HIV infection. JAMA 1989;261:1149.
5. Jacobson MA, Fusaro RE, Galmarini M, et al. Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499. J Infect Dis 1991;164:864-868.
6. Mulder JW, Jos Frissen PH, Krijnen P, et al. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. J Infect Dis 1992;165:413-418.
7. Yang JY, Schwartz A, Henderson EE. Inhibition of Azido-deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro. Biochem Biophys Res Commun 1994;201:1424-1432.
8. Dyner TS, Lang W, Geaga J, et al. An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. J Acquir Immune Defic Synd 1993;6:459-465.
9. Christeff N, Gharakhanian S, Thobie N, et al. Effect of interferon on high serum androgen concentrations in HIV positive men with Kaposi's sarcoma. J Clin Path 1997;50:341-345.
10. Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930.
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