Abstract
With the passage of the U.S. Dietary Supplement Health and Education Act of 1994, dehydroepiandrosterone (DHEA, 5-androsten-3β-ol-17-one) has become widely available, and a large and growing market has developed for this “fountain of youth”. DHEA has been shown to have significant beneficial effects in animals, which may lead to clinical uses in man. Historically, the U.S. Food and Drug Administration removed DHEA from the over-the-counter market in 1985 because there was no support for the health claims that were made for this product. Almost all of the biological data was on animals and there was a lack of demonstrated efficacy in humans. Recently there have been a number of small clinical trials in humans but the results have not been as positive as in the animal tests. This review will be restricted to the effects of DHEA on carcinogenesis, obesity, the immune system, and aging. Four hypotheses have been proposed to explain the underlying biochemical mechanism(s) by which DHEA exerts its beneficial properties. The first is based on the inhibitory effect of DHEA on mammalian glucose-6-phosphate dehydrogenase. This mechanism can explain the antiinitiation and antipromotion steps in some cases of carcinogenesis. The second biochemical mechanism involves the induction of peroxisomes and peroxisome-associated enzymes. The third explanation is that DHEA works in a similar fashion to the known anticarcinogenic action of food restriction. An antiglucocorticoid mechanism has also been suggested. A hypothesis for the increase followed by the decrease in the levels of DHEA with age is proposed. A number of new synthetic DHEA analogs have been synthesized and tested. They offer the best hope for the development of a clinically useful drug based on the properties of DHEA.
Similar content being viewed by others
Abbreviations
- BMI:
-
body mass index
- DHEA:
-
dehydroepiandrosterone (5-androsten-3β-ol-17-one)
- DHEAS:
-
DHEA sulfate
- DMBA:
-
dimethylbenz[a]anthracene
- G6PDH:
-
glucose-6-phosphate dehydrogenase
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
References
Kalimi, M., and Regelson, W. (1990) The Biologic Role of Dehydroepiandrosterone (DHEA), Walter de Gruyter, New York.
Bellino, F.L., Daynes, R.A., Hornsby, P.J., Lavrin, D.H., and Nestler, J.E., eds. (1995) Dehydroepiandrosterone (DHEA) and Aging. Ann. NY Acad. Sci. 774.
Nieuwenhuyse, H., and Thijssen, J.H.H. (1999) DHEA: A Comprehensive Review, Parthenon, New York.
Zumoff, B., and Bradlow, H.L. (1980) Sex Difference in the Metabolism of Dehydroisoandrosterone Sulfate, J. Clin. Endocrinol. Metab. 51, 334–336.
Parker, L.N. (1989) Adrenal Androgens in Clinical Medicine 615 pp., Academic Press, New York.
Orentreich, N., Brind, J.L., Rizer, R.L., and Vogelman, J.H. (1984) Age Changes and Sex Differences in Serum Dehydroepiandrosterone Sulfate Concentrations Throughout Adulthood, J. Clin. Endocrinol. Metab. 59, 551–555.
Coleman, D.L., Leiter, E.H., and Applezweig, N. (1984) Therapeutic Effects of Dehydroepiandrosterone Metabolites in Diabetes Mutant Mice (C57BL/KSJ-db/db), Endocrinology 115, 239–243.
Bulbrook, R.D., Hayward, J.L., Spices, C.C. (1971) Relation Between Urinary Androgen and Corticoid Excretion and Subsequent Breast Cancer, Lancet, 395–398.
Zumoff, B., Levin, J., Rosenfeld, R.S., Markham, M., Strain, G.W., and Fukushima, D. (1981) Abnormal 24-Hr Mean Plasma Concentrations of Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Women with Primary Operable Breast Cancer, Cancer Res. 41, 3360–3363.
Helzlsouer, K.J., Gordon, G.B., Alberg, A.J., Bush, T.L., and Comstock, G.W. (1992) Relationship of Prediagnostic Serum Levels of Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Women with Primary Operable Breast Cancer, Cancer Res. 52, 1–4.
Schwartz, A.G., Whitcomb, J.M., Nyce, J.W., Lewbart, M.L., and Pashko, L.I. (1988) Dehydroepiandrosterone and Structural Analogs: A New Class of Cancer Chemopreventive Agents, Adv. Cancer Res. 51, 391–424.
Schwartz, A.G., Perantoni, A. (1975) Protective Effect of Dehydroepiandrosterone Against Aflatoxin B1 and 7,12-Dimethylbenz[a]anthracence-induced Cytotoxicity and Transformation in Cultured Cells, Cancer Res. 35, 2482–2487.
Schwartz, A.G. (1979) Inhibition of Spontaneous Breast Cancer Formation in Female C3H (Avy/a) Mice by Long-Term Treatment with Dehydroepiandrosterone, Cancer Res. 39, 1129–1132.
Schwartz, A.G., Hard, G.C., Pashko, L.L., Abou-Gharbia, M., and Swern, D. (1981) Dehydroepiandrosterone: An Antiobesity and Anti-Carcinogenic Agent, Nutr. Cancer 3, 46–53.
Schwartz, A.G., and Tannen, R.H. (1981) Inhibition of 7,12-Dimethylbenz[a]anthracene and Urethane Induced Lung Tumor Formation in A/J Mice by Long-Term Treatment with Dehydroepiandrosterone, Carcinogenesis 2, 1335–1337.
Pashko, L.L., Rovito, R.J., Williams, J.R., Sobel, E.L., and Schwartz, A.G. (1984) Dehydroepiandrosterone (DHEA) and 3β-Methylandrost-5-en-17-one: Inhibitors of 7,12-Dimethylbenz[a]anthracene (DMBA)-Initiated and 12-O-Tetradecanoylphorbol-13-acetate (TPA) Promoted Skin Papilloma Formation in Mice, Carcinogenesis 5, 463–466.
Pashko, L.L., Hard, G.C., Rovito, R.J., Williams, J.R., Sobel, E.L., and Schwartz, A.G. (1985) Inhibition of 7,12-Dimethylbenz[a]anthracene-Induced Skin Papillomas and Carcinomas by Dehydroepiandrosterone and 3β-Methylandrost-5-en-17-one, Cancer Res. 45, 164–166.
Helzlsouer, K.J., Alberg, A.J., Gordon, G.B., Longcope, C., and Bush, T.L. (1995) Serum Gonadotropins and Steroid Hormones and the Development of Ovarian Cancer, JAMA 274, 1926–1930.
Heinonen, P.K., Koivlila, T., and Pystynen, P. (1987) Decreased Serum Level of Dehydroepiandrosterone Sulfate in Postmenopausal Women with Ovarian Cancer, Gynecol. Obstet. Invest. 23, 271–274.
Buster, J.E., Casson, P.R., and Straughn, A.B. (1992) Postmenopausal Steroid Replacement with Micronized Dehydroepiandrosterone: Preliminary Oral Bioavailability and Dose Proportionality Studies, Am. J. Obstet. Gynecol. 166, 1163–1170.
Marks, P.A., and Banks, J. (1960) Inhibition of Mammalian Glucose-6-Phosphate Dehydrogenase by Steroids, Proc. Natl. Acad. Sci. USA 46, 447–452.
Raineri, R., and Levy, H.R. (1970) On the Specificity of Steroid Interaction with Mammary Glucose-6-phosphate Dehydrogenase, Biochemistry 9, 2233–2243.
Oertel, G.W., Benes, P. (1972) The Effects of Steroids on Glucose-6-phosphate Dehydrogenase, J. Steroid Biochem. 3, 493–496.
Levin, W., Wood, A.W., Wislock, P.G., Chang, R.L., Kapitulnik, J., Mah, H.D., Yagi, H., Jerina, D.M., and Conney, A.H. (1978) Mutagenicity and Carcinogenicity of Benzo[a]pyrene Derivatives, in Polycyclic Hydrocarbons and Cancer: Environment, Chemistry, and Metabolism (Gelboin, H.V., and Ts'o, P.O.P., eds.) Vol. 1, pp. 189–202, Academic Press, New York.
Emerit, I., and Cerutti, P. (1983) Glastogenic Action of Tumor Promoter Phorbol 12-Myristate-13-acetate in Mixed Human Leukocyte Cultures, Carcinogenesis 4, 1313–1316.
Kinzel, V., Loerke, H., Goerttler, K., Furstenberger, G., and Marks, F. (1984) Suppression of the First Stage of Phorbol 12-Tetradecanoate-13-acetate Effected Tumor Promotion in Mouse Skin by Nontoxic Inhibition of DNA Synthesis, Proc. Natl. Acad. Sci. USA 81, 5858–5862.
Pashko, L.L., Schwartz, A.G., Abou-Gharbia, M., and Swern, D. (1981) Inhibition of DNA Synthesis in Mouse Epidermis and Breast Epithelium by Dehydroepiandrosterone and Related Steroids, Carcinogenesis 2, 717–721.
Wu, H.Q., Masset-Brown, J., Tweedie, D.J., Milewich, L., Frenkel, R.A., Martin-Wixtrom, C., Estabrook, R.W., and Prough, R.A. (1989) Induction of Microsomal NADPH-Cytochrome P-450 Reductase and Cytochrome P-450IVAI (P-450LAω) by Dehydropiandrosterone in Rats: a Possible Peroxisomal Proliferator, Cancer Res. 49, 2337–2343.
Moore, M.A., Weber, E., Thornton, M., and Bannasch, P. (1988) Sex Dependent, Tissue-Specific Opposing Effects of Dehydroepiandrosterone on Initiation and Modulation Stages of Liver and Lung Carcinogenesis Induced by Dihydroxy-di-n-propylni-trosamine in F344 rats, Carcinogenesis 9, 1507–1509.
Tannenbaum, A., and Silverstone, H. (1953) Nutrition in Relation to Cancer, Adv. Cancer Res. 1, 451–501.
Lipman, J.M., Turturro, A., and Hart, R.W. (1989) The Influence in Dietary Restriction on DNA Repair in Rodents: a Preliminary Study, Mech. Ageing Dev. 48, 135–143.
Nakamura, K.D., Duffy, P.H., and Cu, M.H. (1989) The Effect of Dietary Restriction on myc Protooncogene Expression in Mice: A Preliminary Study, Mech. Ageing Dev. 48, 199–205.
Reff, M.E., and Schneider, E.L. (1980) Biological Markers in Aging, National Institutes of Health, Bethesda, Pub. #82-2221.
Sonka, J. (1976) Dehydroepiandrosterone. Metabolic Effects, Acta Univ. Carol. Med., Monogr. 71, 1–137, 146–171.
Bradlow, H.L., Murphy, J., and Byrne, J.J. (1999) Immunological Properties of Dehydroepiandrosterone, Its Conjugates and Metabolites, Ann. NY Acad. Sci. 876, 91–101.
Yen, T.T., Allan, J.A., Pearson, D.V., and Acton, J.M. (1977) Control of Obesity in Avy/a Mice by 5α-Androstan-17-one, Lipids 12, 409–413.
Pashko, L.L., Fairman, D.K., and Schwartz, A.G. (1986) Inhibition of Proteinuria Development in Aging Sprague-Dawley Rats and C57BL/6 Mice by Long-term Treatment with Dehydroepiandrosterone, J. Gerontol. 41, 433–438.
Coleman, D.L., Schwizer, R.W., and Leiter, E.H. (1984) Effect of Genetic Background on the Therapeutic Effect of DHEA in Diabetes-Obesity Mutants and in Aged Normal Mice, Diabetes 33, 26–32.
Cleary, M.P., Shepherd, A., and Jenks, B. (1984) Effect of DHEA on Growth in Lean and Obese Zucker Rats, J. Nutr. 114, 1242–1251.
Cleary, M.P., Fox, N., Lazin, B., and Billheimer, J.T. (1985) A Comparison of the Effects of DHEA Treatment to ad. libitum and Pair Feeding in the Obese Zucker Rat, Nutr. Res. 5, 1247–1257.
Kritchevsky, D., Tepper, S.A., Klurfeld, D.M., and Schwartz, A.G. (1983) Influence of DHEA on Cholesterol Metabolism in Rats, Pharmacol. Res. Commun. 15, 797–803.
Mohan, P.F., and Cleary, M.P. (1988) Effect of Short-term DHEA Administration on Liver Metabolism of Lean and Obese Rats, Am. J. Physiol. 255, E1-E8.
Tchernof, A., Despres, J.P., Belanger, A., Dupont, A., Prud'homme, D., Moorjani, S., Lupien, P.J., and Labrie, F. (1995) Reduced Testosterone and Adrenal C19 Steroid Levels in Obese Men, Metabolism 44, 513–519.
Tchernof, A., Labrie, F., Belanger, A., and Despres, J.P. (1996) Obesity and Metabolic Complications: Contribution of Dehydroepiandrosterone and Other Steroid Hormones, J. Endocrinol. 150, S155-S164.
Mantzoros, C.S., and Georgiadis, E.I. (1995) Body Mass and Physical Activity Are Important Predictors of Serum Androgen Concentrations in Healthy Young Men, Epidemiology 6, 432–435.
De Pergola, G., Zamboni, M., and Sciaraffia, M. (1996) Body Fat Accumulation Is Possibly Responsible for Lower Dehydroepiandrosterone Circulating Levels in Premenopausal Obese Women, Int. J. Obes. Relat. Metab. Dis. 20, 1105–1110.
Votiagtzi, M.G., Boeck, M.A., and Vlachopapadopoulou, E. (1996) Dehydroepiandrosterone in Morbidly Obese Adolescents: Effects on Weight, Body Composition, Lipids, and Insulin Resistance, Metabolism 45, 1011–1015.
Haffner, S.M., Valdez, R.A., and Stern, M.P. (1993) Obesity Body Fat Distribution and Sex Hormones in Men, Int. J. Obes. Relat. Metab. Dis. 17, 643–649.
Vermeulen, A., Kaufman, J.M., and Giagulli, V.A. (1996) Influence of Some Biological Indexes on Sex Hormone Binding Globulin and Androgen Levels in Aging or Obese Males, J. Clin. Endocrinol. Metab. 81, 1821–1826.
Leenen, R., van der Kooy, K., and Seidell, J.C. (1994) Visceral Fat Accumulation in Relation to Sex Hormones in Obese Men and Women Undergoing Weight Loss Therapy, J. Clin. Endocrinol. Metab. 78, 1515–1520.
Nestler, J.E., Barlascini, C.O., and Clore, J.N. (1988) Dehydroepiandrosterone Reduces Serum Low Density Lipoprotein Levels and Body Fat but Does Not Alter Insulin Sensitivity in Normal Men, J. Clin. Endocrinol. Metab. 66, 57–61.
Usiskin, K.S., Butterworth, S., and Clore, J.N. (1990) Lack of Effect of Dehydroepiandrosterone in Obese Men, Int. J. Obes. 14, 457–463.
Welle, S., Jozefowicz, R., and Statt, M. (1990) Failure of Dehydroepiandrosterone to Influence Energy and Protein Metabolism in Humans, J. Clin. Endocrinol. Metab. 71, 1259–1264.
Araneo, B.A., Dowell, T., and Woods, M.A. (1995) DHEAS as an Effective Vaccine Adjuvant in Elderly Humans, in Dehydroepiandrosterone (DHEA) and Aging (Bellino, F.L., Daynes, R.A., Hornsby, P.J., Lavrin, D.H., and Nestler, J.E., eds.) Ann. NY Acad. Sci. 774, 16–28.
Ben-Yehuda, A., Danenberg, H.D., Zakay-Rones, Z., Gross, D.J., and Friedman, G. (1998) The Influence of Sequential Annual Vaccination and of DHEA Administration on the Efficacy of the Immune Response to Influenza Vaccine in the Elderly, Mech. Ageing Dev. 102, 299–306.
Schwartz, A.G., Fairman, D.K., Polansky, M., Lewbart, M.L., and Pashko, L.L. (1989) Inhibition of 7,12-Dimethylbenz[a]anthracene-Initiated and 12-O-Tetradecanoylphorbol-13-acetate-Promoted Skin Papilloma Formation in Mice by Dehydroepiandrosterone and Two Synthetic Analogs, Cancinogenesis 10, 1809–1813.
Mooradian, A.D., Morley, J.E., and Korenman, S.G. (1987) Biological Actions of Androgens, Endocr. Rev. 8, 1–28.
Fernades, G., and Good, R.A. (1984) Inhibition by Restricted-Calorie Diet of Lymphoproliferative Disease and Renal Demage in MRL/lpr Mice, Proc. Natl. Acad. Sci. USA 81, 6144–6148.
Author information
Authors and Affiliations
About this article
Cite this article
Williams, J.R. The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune system, and aging. Lipids 35, 325–331 (2000). https://doi.org/10.1007/s11745-000-0529-7
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11745-000-0529-7