Disabled older women with low or high levels of DHEAS were at greater risk for death over a 5-year period than were women with intermediate levels, even after accounting for multiple other factors associated with mortality. This U-shaped relationship between hormone level and adverse effects is a common paradigm in endocrinology; examples of pairs of disorders representing deficiency and excess include hyperthyroidism, hypothyroidism, Cushing’s syndrome and adrenal insufficiency.
The role of DHEAS in aging has been investigated primarily in terms of the impact of low DHEAS levels, due to their overall gradual decline after puberty. Several studies (18
) have linked low baseline DHEAS levels with cardiovascular disease, muscle weakness, and depressed mood. However, longitudinal studies of individuals older than 65 years have confirmed that 30% of them do not experience a decline in levels (11
). Furthermore, high DHEAS levels have been associated with breast cancer risk (19
); the latter finding, in particular, led us to examine mortality risk associated with both high and low DHEAS levels.
Several studies have examined the relationship between DHEAS levels and mortality in healthier older women. Results from 1171 women aged 65–76 years who participated in the Cambridge General Practice Health Study suggested a U shape (8
). These results were not statistically significant, possibly due to fewer deaths in this younger, healthier population, which had only 10% mortality over the follow-up period, compared to 28% in our study. The Helsinki Aging Study (14
) showed no difference in 5-year mortality rate by age-stratified DHEAS quartiles, though mortality rates in 75-year-old women displayed a U shape. The PAQUID (Personnes Agée QUID) study, which did not allow for a U-shaped relationship, did not show an association between DHEAS levels and mortality (10
). In a preliminary report from the Rancho Bernardo Study (12
), a U-shaped relationship was seen between DHEAS and cardiovascular mortality, though not all-cause mortality. Subsequent analyses with longer follow-up have shown no relationship between DHEAS and cardiovascular mortality, though models allowing for a nonlinear relationship were not used (13
). The use of models allowing for a nonlinear relationship is critical in analyzing hormonal data. As illustrated in previous studies and ours, a link between DHEAS and mortality was not present in models using DHEAS as a linear variable, but became apparent when nonlinear associations were permitted. Our study, in contrast to the previous studies, does not ignore the underlying biologic paradigm, allowing our models to represent most accurately the distribution of DHEAS data.
Our results suggest two interpretations: Deficiency or excess of DHEAS mediates adverse effects that increase mortality risk, or DHEAS is a marker of health status, without any pathogenic effects of its own. Mechanistic data support a potential physiologic role of DHEAS in mortality risk. DHEAS may have anti-inflammatory properties, decreasing cardiovascular risk; immune regulatory activity, improving autoimmunity; or it may be converted to estrogen, promoting hormone-responsive cancers (4
). Our cause-specific mortality data, though preliminary, support these specific pathways of DHEAS effects. However, examples also exist of hormonal deficiencies in response to coexistent illness, such as the nonthyroidal illness (euthyroid sick) syndrome, correction of which has not consistently resulted in beneficial outcomes (33
). Indeed, in a small study of younger individuals undergoing cholecystectomy, DHEAS levels declined significantly within 1 week of this acute stress, though longer follow-up was not available (34
). Conversely, adrenocorticotropic hormone-dependent stimulation of adrenal androgen synthesis is present, though blunted, with age (35
); thus, it is possible that high DHEAS levels are a marker of physiologic stress. This possibility is supported by data from a small study of older patients in whom DHEAS levels rose immediately following cardiac surgery and returned to baseline levels within 30 days (36
). Although we adjusted for multiple potential confounders, including 10 different comorbid diseases, we cannot exclude the possibility that DHEAS levels represent indicators of health status. Studies of disabled women that assess the impact of altering DHEAS levels toward an optimal level are required to distinguish between these possibilities and to clarify the role of DHEAS in disability and old age.
We identified a U-shaped relationship using several different modeling strategies and after adjustment for multiple factors. WHAS I, a cohort designed to represent the one-third most disabled women living in the community, comprised a group of women who are in need of beneficial interventions. The use of sampling from the HCFA database instead of a volunteer recruitment mechanism and home visits instead of travel to a study clinic enabled us to enroll and closely follow a representative sample of women who ordinarily exclude themselves or are excluded from research studies. Although DHEAS is the major circulating form of the hormone, DHEA is the formulation used in exogenous administration. Interventional studies of DHEA in adults with adrenal insufficiency have demonstrated clear benefits in lean body mass, bone mineral density, mood, and fatigue (4
). Data in healthy older individuals, however, do not consistently support benefits of DHEA therapy (4
). The largest randomized, placebo-controlled trial, the DHEAge Study, included 140 men and 140 women aged 60–79 years randomized to DHEA or placebo for 1 year. No benefits were found in muscle strength, muscle cross-sectional area, cognition, or well-being in healthy older men and women, but a slight improvement was seen in bone mineral density and libido in women > 70 years (35
). Recent preliminary data from a randomized trial of 56 men and women treated with DHEA for 6 months showed decreases in visceral fat and improvements in insulin sensitivity, emphasizing the need for continued research in this area (38
There are many unanswered questions regarding the appropriate target population for DHEA therapy. Classified as a dietary supplement, DHEA has not undergone the U.S. Food and Drug Administration (FDA)–mandated testing required of other hormones, despite widespread usage without medical supervision. Furthermore, it is not required to be manufactured in compliance with the FDA’s Good Manufacturing Practices, with one study showing that only 7 of 16 tested preparations had DHEA content within 90%–110% of the labeled claim (39
). No trials have continued for more than 1 year, included hard clinical endpoints, or studied the relevant population of older people with disability, raising questions regarding its long-term risk/benefit ratio, particularly given the potential harm from raising tissue levels of estrogen and testosterone. Our data do not suggest that older women with higher endogenous DHEAS levels have greater longevity. Rather, the disabled older women studied here with higher levels had higher mortality, as did those with the lowest levels. Although this was an observational study, these data suggest that administration of additional DHEA to women with higher DHEAS levels through supplements would not be beneficial, and would be potentially harmful. More research is needed to determine if targeted DHEA supplementation would provide clinical benefit to disabled older women. At present, there is insufficient evidence from our study and others to recommend DHEA supplementation to improve the health status of older individuals.