ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCESOffice of Population Research Princeton University WORKING PAPER SERIES New evidence for protective effects of DHEAS on health among men but not women Working Paper No. 2006-05 Noreen Goldman* Dana A. Glei† Last Revised: July 31, 2006 * Corresponding author: Office of Population Research, Princeton University, 243 Wallace Hall, Princeton, NJ 08544-2091, USA. E-mail: [email protected]. Tel: (609) 258-5724. Fax: (609) 258-1039. † Department of Demography, University of California, Berkeley, 1512 Pembleton Place, Santa Rosa, CA 95403-2349, USA Abbreviations: DHEA=Dehydroepiandrosterone; DHEAS=Dehydroepiandrosterone-sulfate; SEBAS=Social Environment and Biomarkers of Aging Study; CES-D= Center for Epidemiologic Studies Depression scale Papers published in the OPR Working Paper Series reflect the view of individual authors. They may not be cited in other publications, but are intended to be work-in-progress. Comments are welcome. 1ABSTRACT The adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) have been the focus of considerable publicity in recent years because of their demonstrated associations with a broad range of health outcomes. Yet, despite a large literature examining the health consequences of DHEA(S), few have been based on prospective surveys of population-representative samples. Thus, our knowledge about the causal effects of DHEA(S) on health in humans is limited and often inconclusive. In this analysis, we use a national longitudinal survey in Taiwan to explore the associations between DHEAS and changes over a 3-year period in functional limitations, cognitive impairment, depressive symptoms, and global self-rated health for men and women. Our estimates suggest that, for the older Taiwanese population, DHEAS is related to subsequent declines in mobility and increased depressive symptoms among men, but there are no significant associations between DHEAS and women’s mental and physical health. These findings differ from those in a previous cross-sectional analysis based on the Taiwan study and underscore the importance of using prospective rather than cross-sectional data to examine the effects of DHEAS on health. The evidence to date from this study and other investigations based on longitudinal data suggests that DHEAS is protective of some health outcomes for men, but not women, in both Western and non-Western populations and raises questions about what factors give rise to these sex differences. 2INTRODUCTION The adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) have been the focus of considerable publicity in recent years because of their demonstrated associations with a broad range of health outcomes and extrapolated claims that, taken as nutritional supplements, they may enhance longevity. These inactive prohormones are secreted in large amounts by the adrenal cortex only in humans and in other primates and are converted to androgens and estrogens in peripheral tissues (1). The steady decrease in serum levels of these steroids from early adulthood onwards suggests that they may be markers of aging and that high levels may protect against the pathological consequences of becoming old. Animal experiments reveal broad-ranging health effects of DHEA and DHEAS, and experimental and observational studies on humans demonstrate statistically significant associations with survival and various measures of health status, including diabetes, cardiovascular disease, obesity, cognitive impairment, physical limitations and depressive symptoms (see, for example, 2-8). In light of the fact that DHEA and DHEAS are precursors to sex hormones, it is not surprising that there appear to be important differences between men and women. Virtually all studies find that the concentration of these steroids is much higher in men than in women and many find that the associations between DHEA(S) and health or survival vary by sex. However, these latter findings are often contradictory, with some studies suggesting associations only among males, others finding no significant differences by sex, and two studies reporting stronger associations among women than men for selected outcomes (5, 9). Despite extensive research on these steroids, little is known about their specific functions or the mechanisms by which they affect health (10). Research suggests that DHEA may counterbalance the immunosuppressive effects of glucocorticoids, although the receptor for DHEA has not been fully characterized (11). DHEA has been shown to have biological actions on hemostasis, cell proliferation, lipid metabolism, stress response, and immune function (6, 12). Knowledge about causal effects of DHEA(S) for health in humans is limited and often inconclusive for several reasons: many of the experimental studies have been performed on non-primates, which have far lower concentrations of these steroids than humans (13, 14); experimental studies in humans have typically involved short-term administration of pharmacological doses, small samples, and subjects with various disorders, such as adrenal insufficiency (13-18); and observational studies of humans have been primarily cross-sectional, preventing researchers from separating what are believed to be the effects of certain illnesses on DHEA(S) levels from the sought after effects of DHEA(S) on health status (19, 20). Surprisingly few studies have been based on prospective surveys of population-representative samples, despite the advantage of this research design for investigating the effects of endogenous levels of DHEA(S) on health in the general population (5, 6, 21, 22). Moreover, virtually all of the longitudinal population-based surveys that have been carried out are based on community samples of (predominantly) whites in the United States or Western Europe, thereby limiting generalizations to broader populations because of racial and ethnic differences in concentrations of DHEAS and adrenal metabolism (19, 22). Many have additional limitations, including restriction to one sex 3(6, 23, 24) and small, selective, or non-representative samples (e.g., high non-response rates, selection of healthy subjects, and non-random selection from larger samples; 5, 7, 23, 25-27). In addition, many of these surveys focus on survival, providing less information on the consequences of varying levels of