DHEA: Panacea or snake oil? Sandra M. Sirrs, MD, FRcPc Richard A. Bebb, MD, FRCPC
OBJECTIVE To review the evidence that supplementation with dehydro-3-epiandrosterone (DHEA) is beneficial in aging, cardiovascular disease, immune function, and cancer. METHODS English-language literature search using MEDLINE with subject headings DHEA, adrenal steroids, and androgens. QUALITY OF EVIDENCE Although some randomized, double-blind, placebo-controlled trials have been conducted, most of the evidence supporting use of DHEA for any disease state is of poor quality and consists of case reports and case-control and open-label clinical trials. MAIN MESSAGE Dehydro-3-epiandrosterone is available as a health food supplement and is touted as being beneficial for a variety of diseases. It might be beneficial for improving someone's sense of well-being; minor improvements in body composition have been noted for men only. No consistent relationship has been demonstrated between levels of DHEA and risk of cardiovascular disease, breast cancer, or immune function. Insufficient evidence exists to support using DHEA for acquired immune deficiency syndrome. High levels of DHEA are associated with adverse effects, such as increased risk of breast and ovarian cancer at certain ages and reduced levels of high-density lipoprotein cholesterol. CONCLUSIONS Current enthusiasm for using DHEA as a panacea for aging, heart disease, and cancer is not supported by scientific evidence in the literature. Given the potentially serious adverse effects, using DHEA in the clinical setting should be restricted to well-designed clinical trials only. OBJECTIF Revoir les donnees probantes 'a l'effet que la supplementation en dehydroepiandrosterone 3 (DHEA) est benefique chez les personnes agees, dans les cas de maladies cardiovasculaires et de cancer, et pour la fonction immunitaire. METHODES Une recension des ouvrages scientifiques en anglais dans MEDLINE, a I'aide des mots et cles dans cette langue pour DHEA, corticosteroides et androgenes. QUALITE DES DONNEES Quoique certains essais aleatoires a double insu contre placebo aient ete realises, la majorite des donnees probantes favorables 'a l'utilisation du DHEA, pour tout etat pathologique quel qu'il soit, sont de qualite mediocre et consistent en des rapports de cas, ou des essais cliniques ouverts et de cas
t6moins. PRINCIPAL MESSAGE Le dehydroepiandrosterone 3 est disponible comme supplement alimentaire et pretendu benefique contre diverses maladies. II peut se reveler efficace pour augmenter la sensation de bienetre; des ameliorations mineures dans la constitution du corps ont ete observees chez les hommes seulement. Aucun rapport coherent n'a ete demontre entre les taux de DHEA et le risque de maladies cardiovasculaires, de cancer du sein ou de troubles de la fonction immunitaire. II n'existe pas de donnees probantes suffisantes pour justifier le recours au DHEA dans les cas de syndrome de l'immunodeficience acquise. Des taux eleves de DHEA sont associes 'a des effets indesirables, comme le risque accru, 'a certains ages, de cancer du sein ainsi que des ovaires, et a des taux reduits de cholesterol lipoproteinique a densite elevee. CONCLUSIONS Uenthousiasme actuel pour l'utilisation du DHEA comme une panacee contre le vieillissement, les maladies cardiaques et le cancer n'est pas justifie par des donnees probantes scientifiques dans les ouvrages en la matiiere. Compte tenu des graves effets secondaires du DHEA, il faudrait limiter exclusivement son recours, dans le milieu clinique, aux essais cliniques bien concus.
7his article has been peer reviewed. Cet article a fait l'objet d'une evaluation externe. Can Fam Physician 1999;45:1723-1728. VOL45: JULY * JUII1ET 1999 0Canadian Family Physician Le Medecin defamille canadien
DHEA: Panacea or snake oil?
ehydro-3-epiandrosterone (DHEA) is the main steroid hormone secreted by the adrenal gland.' Dehydro-3-epiandrosterone is intermediate in the production of both androgens and estrogens (Figure 1).2 It exists in equilibrium with its sulfated form, DHEAS. Because DHEA and DHEAS exist in serum at much higher concentrations than other steroid hormones, DHEA has been viewed as a storage repository from which the more potent sex hormones can be formed as necessary.12 A physiologic role for DHEA, other than as a precursor to sex hormones, has not been defined. In fact, no DHEA receptor has ever been identified, and hence its action might be exclusively through conversion to other hormones. Despite this lack of knowledge, there has been a great deal of interest in the lay and medical press concerning potential therapeutic uses for DHEA. The compound is widely available in health food stores in the United States where it is marketed as a dietary supplement.3 Canadian patients can acquire DHEA through US health food stores, but the compound is not available legally in health food stores in Canada. This article reviews the literature concerning the relationship between DHEA and aging, cardiovascular disease, immune function, and cancer.
Quality of evidence A search of the English-language literature was performed using MEDLINE and the subject headings DHEA, adrenal steroids, and androgens. Except where otherwise noted, only literature pertaining to human subjects was reviewed. Priority for inclusion in this article was given to randomized, blinded clinical trials with appropriate control populations, but because very few such trials exist, less rigorous data available from case reports and observational and case-control studies are also included. Only literature pertaining to DHEA and aging, cardiovascular disease, immune function, and cancer was included, although other interesting literature concerning other disease processes and the physiology of DHEA is available. Main findings Aging. Promoted as the "fountain of youth," DHEA is available over-the-counter in US health food stores Drs Sirrs and Bebb teach in the Division of Endocrinology at the University of British Columbia in Vancouver, BC. Dr Sirrs is on staff at the Vancouver General Hospital; Dr Bebb is on staff at St Paul's Hospital.
as a dietary supplemene and is in widespread use as an antidote to aging. Data on prevalence of DHEA use in Canada are not available. Serum DHEA levels are highest in the third decade of life and then decline at a rate of approximately 2% per year, so that by the eighth decade, levels might only be 1% to 20% of normal values among younger people.45 This decrease is largely the result of decreased adrenal secretion6: the rate of decrease is highest before age 60; after that, decline in DHEA levels is more gradual.7 Morales et al conducted a randomized, placebo-controlied trial using 50 mg/d of DHEA in 30 patients aged 40 to 70 years8 and found that this dose returned levels of DHEA and DHEAS to normal values. Associated with use of DHEA was a significant improvement in subjects' sense of well-being, including better sleep, increased energy, and better ability to handle stress. This same group conducted another randomized trial using 100 mg/d of DHEA for 1 year in 16 men and women older than 509 and found improvement in muscle strength and body fat mass, which was significant only for men. Neither study evaluated the effect of DHEA on cognitive indices. Because these are the only randomized, double-blind, placebo-controlled trials that evaluate the effects of DHEA on aging, it is clear that claims that DHEA can prevent memory loss and slow progression of age-related conditions, such as Alzheimer's or Parkinson's diseases, are not supported by available scientific evidence.3
Cardiovascular disease. A great deal of conflicting epidemiologic data have been published describing the relationship of DHEA to cardiovascular disease and cardiovascular risk factors. To interpret these data, it is necessary to conceptualize the relationship between DHEA and the other sex steroids, such as testosterone and estradiol. A succinct hypothesis has been proposed by Ebeling and Koivisto,l who propose that the relative androgenic or estrogenic properties of DHEA vary with the ambient hormonal milieu. For example, in men with normal testosterone levels, DHEA could have predominantly estrogenic effects. In premenopausal women, who have an estradiol-dominant environment, DHEA is likely to function as an estrogen antagonist (because a DHEA metabolite, androstenediol, can compete with estradiol for binding to the estrogen receptor, Figure 1) or be converted to androstenedione and testosterone to function as an androgen. In postmenopausal women, it is difficult to predict what the net effect of DHEA might be. Conversion of DHEA to androgens could
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further reduce the ratio of estrogen to androgen and might, therefore, have deleterious cardiovascular effects. Or for women who have low estradiol levels, DHEA might have a net estrogenic effect. Bearing these relationships in mind, it is important to evaluate information about DHEA according to the sex and age of study subjects. Starting first with male subjects, a prospective observational study involving 1029 men followed for 19 years found an inverse relationship between serum DHEAS levels and the risk of death from cardiovascular disease.'0 This relationship was modest (relative risk [RR] 0.85), but statistically significant. Other prospective studies have failed to confirm this relationship.'1 Post-hoc analysis of data from the Helsinki Heart Study showed that DHEAS levels were higher in patients who suffered cardiac events than in those who did not,'2 but this relationship was significant only for subjects older than 47 or for smokers. Further, the Helsinki Heart Study data show that DHEAS is strongly correlated with traditional cardiovascular risk factors, such as age, high-density lipoprotein (HDL) cholesterol levels, triglycerides, smoking, and blood pressure, thereby weakening the argument that DHEAS itself independently influences cardiovascular risk.'2 A less powerful retrospective case-control study involving 49 young male survivors of myocardial infarction showed that DHEAS levels were
significantly lower in these men than in agematched controls, after matching for other cardiovascular risk factors.'3 Data from the Honolulu Heart Program, a prospective study of more than 8000 Japanese men, is even more confusing in that DHEAS levels were lower among those who had fatal coronary heart disease than among controls, but no association between DHEAS and non-fatal coronary events was found.'4 In contrast to the data for men, the data for women are more uniform in that most studies suggest that DHEAS level does not affect cardiovascular risk in postmenopausal women. In a case-control evaluation of 942 postmenopausal women who were part of the Rancho Bernardo cohort, no association between DHEAS levels and cardiovascular mortality was found."5 Other data from this same female cohort show that elevated DHEAS levels are associated with increased prevalence of adverse cardiovascular risk factors, such as abdominal obesity, impaired glucose tolerance, and diabetes.'6 These epidemiologic data, when combined with the observation that treatment with 50 mg of DHEA reduced HDL-cholesterol levels in women,8 strongly argue against women using DHEA supplements. One prospective observational study" did suggest that low levels of DHEAS predicted death from ischemic heart disease in postmenopausal women with diabetes, but this observation cannot be used as a basis
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for therapy in light of the adverse metabolic consequences observed by other investigators.8 Observational studies, while providing information that can support generation of hypotheses, are no substitute for randomized trials. No appropriately randomized trials of DHEA investigate whether using it is associated with a reduction in cardiovascular events. In the absence of such trials, use of DHEA to prevent cardiovascular disease cannot be condoned, even for men in whom beneficial effects could be postulated on the basis of some epidemiologic data. Immune function. Low levels of DHEAS are consistently found during physiologic stress because the adrenal glands maintain high levels of cortisol production at the expense of other adrenal steroids, such as DHEA. Although some in vitro immunomodulatory effects of DHEA, such as altered interleukin production and lymphocyte differentiation, have been demonstrated, it seems more plausible that the lower levels of DHEAS during illness are the result, not the cause, of physiologic stress.6 It is notable that many of the animal studies that evaluate DHEAs effect on immune function have been done on rodents whose endogenous DHEA production is minimal, and thus the data are not readily extrapolated to humans. Nevertheless, because of the in vitro data, use of this agent in patients with immune-mediated conditions has been evaluated. Danenberg et al,'7 who had previously shown beneficial effects in a mouse trial, conducted a randomized, double-blind study of 71 subjects (mean age 73 years) to see whether DHEA would enhance patients' antibody response to influenza vaccine."7 Unlike results in their mouse trial, there were no beneficial effects on humans. Another trial'8 with older patients (mean age 78.6 years) did show that DHEA supplementation improved response to influenza vaccination, although this finding was limited to subjects with low prevaccination antibody titres and was of borderline statistical significance (P=.06). Clearly, more work needs to be done in this area before DHEA* supplementation can be recommended as adjuvant therapy for patients undergoing vaccination. In a randomized, double-blind, placebo-controlled trial,'9 DHEA was evaluated as a therapeutic agent in autoimmune disease, such as systemic lupus erythematosus, where use of 200 mg/d of DHEA reduced disease activity and allowed a concomitant reduction in prednisone dose for 28 women with mild to moderate disease. It should be noted, however, that the disease severity index used in this trial relies in part on patients' assessment of disease, although other
objective measures of disease are also incorporated into the rating scale. Because the trial used some subjective measures of disease improvement, it is possible that some of the observed beneficial effects were related to DHEA's effect on mood, rather than its effect on joint inflammation per se. Anecdotal reports of reduced proteinuria related to DHEA use in patients with lupus nephritis have been published,20 but systematic trials have not been carried out. Taken together, these data suggest that endogenous DHEA might serve an immunomodulatory function, although more research is required before the therapeutic usefulness of this agent can be defined. Acquired immune deficiency syndrome. There has been some interest in the relationship between DHEA and AIDS. As summarized in a recent review, DHEA has been shown in animal models to increase levels of interleukin-2, which might help guard against acute viral illness.2' Low levels of DHEA have been associated with an increased risk of disease progression in asymptomatic HIV-positive subjects22 and in HIV-positive subjects with CD4 cell counts of 200 to 499 cells/mmnu Laudat et al24 documented that DHEA levels were directly correlated with CD4 cell count, but the ratio of cortisol to DHEA was inversely related to CD4 count, suggesting that adrenal steroid production shifts from androgen to cortisol as illness progresses. It is likely, then, that the changes observed in DHEA levels are a physiologic response to, not cause of, chronic illness. No available long-term clinical trials support use of DHEA therapy to alter disease outcome in HIV-infected patients.
Cancer. Some epidemiologic data link DHEA to various cancers. High levels of DHEA and androstenedione were associated with an increased risk of ovarian cancer in a nested case-control study from Maryland.25 Interestingly, in this study, the association between androgens and ovarian cancer was significant only for premenopausal women, underscoring the fact that DHENs effects might vary according to the prevailing hormonal environment The relationship of DHEA to breast cancer also varies with age. As discussed above, in premenopausal women with a predominantly estrogenic milieu, DHEA might be expected to function as an estrogen antagonist, but it might function as an estrogen agonist in the low-estrogen environment of postmenopausal women.' Consistent with this theory are data that show that low levels of DHEA are
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associated with increased risk of breast cancer in premenopausal women,26 but high levels of DHEA increase the risk of breast cancer in postmenopausal women.27 Analogues of DHEA that cannot be further converted to androgens and estrogens have been developed for clinical trials of cancer prevention.28 Other potential uses for DHEA Some researchers are interested in using DHEA to treat obesity. As mentioned above, administering 100mg/d of DHEA to aging subjects for 1 year was associated with a reduction in fat mass that was significant for men, but not for women.9 A larger dose (400mg/d) reduced fat mass in nonobese young subjects,' but no effects on fat mass were observed when a much larger dose (1600 mg/d) was given in a placebo-controlled study of young obese subjects.30 These discrepant results might be related to the different doses used or to differences in the prevailing hormonal milieu of obese and nonobese subjects. It is reasonable to conclude, however, that DHEA treatment of obese patients has not had obvious benefits. Enhanced cognition and mood has been reported in a small open-label study of depressed patients' use of DHEA31; these findings have not yet been confirmed by more rigorous trials. It is plausible to postulate that DHEA, a precursor of estradiol, influences cognition in light of recent information supporting estrogen's beneficial effects on mood32 and memory,33 and its protective effect on risk of Alzheimer's disease.34 In fact, DHEA has been shown to block -taminobutyric acid (a neurotransmitter) receptors, which might be one way it could affect cognition and memory.35 Until further studies of the effect of DHEA on cognition are available, however, its use can not be recommended in light of the adverse effects described above. Panacea or snake oil? It is clear from the studies presented that, while some provocative data suggest that DHEA plays a role in many physiologic functions, few data support its use in the clinical seting. By marketing DHEA as a nutritional supplement in the United States, companies can bypass the rigorous clinical trials required for approval for medicinal use of any substance. Nutritional supplements are also not subject to the strict quality control measures applied to drugs. Thus, not only is there little evidence to support use of DHEA, patients who choose to use it have no control over the quality of the product they receive. John Nestler, an endocrinologist from Virginia and organizer of a 1995 conference on DHEA and aging, likened DHEA to snake oil because of
Key points * Dehydro-3-epiandrosterone (DHEA) has become a popular natural food supplement with many alleged properties. * The literature on DHEA is mostly case reports, and case-control or open-label studies. There are very few clinical trials. * Some evidence suggests that DHEA enhances men's sense of well-being, but no good evidence suggests it protects men or women against coronary artery disease of HIV infection or women against breast cancer. * Using DHEA might increase risk of breast an'd ovarian can.cer and might reduce levels of highdensity lipoprotein cholesterol. * Panacea? Don't think so! widespread and largely unsubstantiated claims made about the putative effects of the hormone.3 It is important to ask our patients whether they use health food supplements and to provide them with the information necessary for them to make educated decisions about such use. Conclusion Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the prevailing hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of premenopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically, DHEA might be useful for improving older people's psychologic well-being and possibly for reducing disease activity in people with mild to moderate systemic lupus erythematosus. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials support these claims and the safety of long-term DHEA supplementation has not been completely established. Elizabeth Barrett-Connor, senior author of one of the first pivotal studies that aroused interest in DHEA,10 made the following statement in 1995. It aptly summarizes the current status of DHEA in the medical armamentarium: "Every 5 years a new wonder drug comes along. I don't think DHEA is the wonder drug people seem to think it is."
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Correspondence to: Dr R.A. Bebb, 416-1033 Davie St, Vancouver, BC V6E 1M7; telephone (604) 689-1055; fax (604) 689-2955; e-mail [email protected]
References 1. Ebeling P, Koivisto VA Physiological importance of dehydroepiandrosterone. Lancet 1994;343:1479-81. 2. White PC, Pescovitz OH, Cutler GB. Synthesis and metabolism of corticosteroids. In: Becker, editor. Principles and practice of endocrinology and metabolism. Philadephia, Pa: JB [ippincott Co; 1995. p. 647-62. 3. SkolnickAA. Scientific verdict still out on DHEA. JAMA 1996; 276:1365-7. 4. Orentreich N, Brind JL, Rizer RI, Vogelman JH. Age changes and sex differences in serum DHEAS concentrations throughout adulthood.J Clin Endocrinol Metab 1984;59:551-5. 5. BelangerA, Candas B, DupontA, Cusan L Diamond P, GomezJI, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40 to 80 year old men.J Clin Endocrinol Metab 1994;79:1086-90. 6. Baulieu EE. Dehydroepiandrosterone (DHEA): a fountain of youth?J Clin Endocrinol Metab 1996;81:3147-51. 7. Labrie F, BelangerA, Cusan L GomezJL, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997;82:2396.402. 8. Morales AJ, Nolan JJ, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.J Clin Endocrinol Metab 1994;78:1360-7. 9. Yen SSC, Morales AJ, Khorram 0. Replacement of DHEA in aging men and women: potential remedial effects. Ann N YAcad Sci 1995;774:128-42. 10. Barrett-Connor E, Khow KT, Yen SSC. A prospective study of DHEAS, mortality, and cardiovascular disease. NEnglIJMed 1986;315:1519-24. 11. Haffner SM, Moss SE, Klein BEK Klein R Sex hormones and DHEA-S04 in relation to ischemic heart disease mortality in diabetic subjects: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabet Care 1996;19:1045-50. 12. Hautanen A, Manttari M, Manninen V, Tenkanen L, Huttunen JK Frick MH, et aL Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Atherosclerosis 1994;105:191-200. 13. Mitchell LE, Sprecher DL, Borecki IB, Rice LT, Laskarzewski PM, Rao DC. Evidence for an association between dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males. Circulation 1994;89:89-93. 14. LaCroixAZ, Yano K, Reed DM. Dehydroepiandrosterone sulfate, incidence of myocardial infarction, and extent of atherosclerosis in men. Circulation 1992;86:1529-35. 15. Barrett-Connor E, Goodman-Gruen D. Dehydroepiandrosterone sulfate does not predict cardiovascular death in post-menopausal women: the Rancho Bernardo Study.
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17. Danenberg HD, Ben-Yehuda A, Zakay-Rones Z, Gross DJ, Friedman G. Dehydroepiandrosterone treatment is not beneficial to the immune response to influenza in elderly subjects.JClin Endocinnol Metab 1997;82:29114. 18. DegelauJ, Guay D, Hallgren H. The effect of DHEAS on influenzavaccination in aging adults.JAm Geriatr Soc 1997;45:747-51. 19. van Vollenhoven RF, Engleman EG, McGuire JL Dehydroepiandrosterone in systemic lupus erythematosus. Aritis Rheum 1995;38:1826-31. 20. van Vollenhoven RF, Engleman EG, McGuire JL An open study of dehydroepilandrosterone in systemic lupus erythematosus.Arthritis Rzeum 1994;37:1305-10. 21. Centurelli MA, Abate MA The role of dehydroepiandrosterone in AIDS. Ann Pharmacother 1997;31:639-42. 22. MulderJW, Frissen PHJ, Krijnen P, Endert E, de Wolf F, GoudsmitJ, et aL Dehydroepiandrosterone as a predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected mien.J Infect Dis 1992;165:413-8. 23. Jacobson MA, Fusaro RE, Galmarini M, Lang W. Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499. JInfect Dis 1991;164:864-8. 24. LaudatA, Blum 1L GuechotJ, Picard 0, CabaneJ, ImbertJC, et al Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts. EurJEndocrinol 1995; 133:41&24. 25. Helzlsouer KJ, Alberg AJ, Gordon GB, Longcope C, Bush TI, Hoffman SC, et aL Serum gonadotropins and steroid hormones and the development of ovarian cancer.JAMA 1995;274:1926-30. 26. Zumoff B, Levin J, Rosenfeld RS, Markham M, Strain GW, Fukushima DK Abnormal 24-hr mean plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate in women with primary operable breast cancer. CancerRes 1981; 41:3360-3. 27. Gordon GB, Bush TI, Helzlsouer KJ, Miller SR, Cumstock GW. Relationship of serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing postmenopausal breast cancer. Cancer Res 1990;50:3859-62. 28. Kelloff GJ, Malone WF, Boone CW, Sigman CC, FayJR Progress in applied chemoprevention research. Semin Oncol
1990;17:438-55. 29. NestlerJE, Barlascini CO, CloreJN, Blackard WG. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men.J Cain Endocnnol Metab 1988;66:57-61. 30. Usiskin KS, Butterworth S, Clore JN, Arad Y, Ginsberg HN, Blackard WG, et aL Lack of effect of dehydroepiandrosterone in obese men. Intj Obesity 1990;14:457-63. 31. Wolkowitz OM, Reus VI, Roberts E, Manfredi F, ChanT, Raum WJ, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Pschiatry 1997;41:311-8. 32. MortolaJF. Estrogens and mood.JSOGC 1997;(Oct Suppl):1-6. 33. Sherwin BB, Carlson LE. Estrogen and memory in women. JSOGC 1997;(Oct Suppl):7-13. 34. Henderson VW, Paganini-Hill A Estrogen and Alzheimers disease.JSOGC 1997;(Oct Suppl):21-8. 35. Majewska MD. Neuronal actions of dehydroepiandrosterone: possible roles in brain development, aging, memory, and affect. Ann N YAcad Sci 1995;774:111-20.
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