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Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) are the most abundant steroids produced by the human adrenal gland. DHEA-S, sometimes considered as a plasma "reservoir" for the hormone, appears in the circulation at about one thousand times the concentration of DHEA, is water soluble, and is capable of being bound to albumin. Although it is DHEA that has been identified as having biological activity, the cellular receptor for, and molecular mode of action of, DHEA and DHEA-S remains uncertain. Depending upon the species and tissue, the possibilities for the former seem to include the NMDA sigma receptor, the GABAA receptor, the estrogen receptor, and the PPAR alpha receptor. In addition, and further complicating the situation, is the possibility that DHEA and DHEA-S work indirectly on target tissues, either following conversion into more potent steroids (including estrogen and testosterone), through another mediator, or as an antagonist to still another potent steroid, cortisol.

DHEA and DHEA-S are synthesized in large amounts by the fetal adrenal gland, with the levels dropping dramatically in newborn and in children. Beginning in about middle -adolescence, and coincident with the development of the zona reticularis in the adrenal cortex, the levels begin to rise sharply again. This onset of heightened activity of the adrenal gland is referred to as adrenarche. At about puberty, the blood hormone levels in boys and girls are similar; thereafter the serum concentration in males begins to exceed that of females. In both sexes, the levels of circulating DHEA and DHEA-S reach their peak during young adult life. Subsequently, in humans and other higher primates, the levels of DHEA and DHEA-S undergo, on average, a steady decline with advancing age. In humans, this decline in circulating hormone reaches about 30 percent of young adult levels by about age 65 years and about 10 percent by age 85 and older. The reduction in DHEA/DHEA-S is thought to result, at least in part, from an involution of the zona reticularis. The latter, age-associated change in adrenal gland structure and DHEA production is referred to as adrenopause.

In spite of the substantial individual-to-individual variation in hormone levels, the progressive decline of these levels with age has led to consideration of DHEA and DHEA-S as biomarkers of the aging process; that is, as chemical indicators useful in tracking age-related senescent change, morbidity, and mortality. More importantly, the decline in levels of these two closely related steroids has also been implicated as being responsible, at least in part, for many of the senescent changes seen in advanced-aged individuals and in individuals with chronic illness. These changes include, but are not limited to, body composition, some forms of cancer, type II diabetes, atherosclerosis and ischemic heart disease. At least some of these associations are sex specific, though not always in a readily understood manner. For example, DHEA-S appears to be related to body composition (fat and lean body mass) in men but not in women. On the other hand, a similar association of DHEA to body composition may be present in women (17). Whatever the limitations and contradictions in the existing literature, it is the notion that diminished hormone levels in older persons are causally linked to age-related functional decline and structural change that has provided the rationale for the well-promoted use of DHEA as an "anti-aging" intervention. In the United States, DHEA is readily available without prescription. However, clinical data documenting the usefulness of DHEA supplementation in humans is limited to very few examples. As of 2001, most of the impressive findings reported on the effects of DHEA treatment have come from studies in rodent models of aging and senescent change; not from human subjects.

Systemic lupus erythematosus (SLE) appears to be one circumstance where taking DHEA benefits the patient. Using the steroid has been reported to reduce the symptoms of SLE and to permit lowering the dose of corticosteroid used to treat the disease. The latter is important because of the potential negative side effects associated with the chronic use of corticosteroids. DHEA may also be useful in the treatment of major depression. Barrett-Conner et al. (1995) found endogenous DHEA-S levels to be significantly and inversely associated with depressed mood. This finding compliments an earlier report that modest doses of DHEA over four weeks improves depression ratings in patients with major depression and low plasma DHEA-S values.

Even though hormone replacement seems a rational approach for ameliorating the possible negative consequences of naturally occurring, age-related declines in hormone levels, the only circumstance in which there is clear documentation supporting such a strategy is estrogen replacement in postmenopausal women. Even here, however, the approach remains controversial because of the risk of increasing the incidence of cancer in estrogen sensitive tissues. The justification for using DHEA in hormone replacement is (as of 2001) much weaker, with the prevailing view being that more long-term, carefully controlled, and larger clinical trials are needed before such action can be justified. In particular, more work is needed to confirm those special circumstances where initial findings are promising, such as the treatment of major depression. In addition, there appears to be growing support for the idea of using DHEA to help mitigate the negative side effects of corticosteroids (e.g., prednisone) in patients where the latter are an essential part of therapy (e.g., for chronic inflammatory disease and SLE). Thus, while no compelling reasons can be found for recommending DHEA supplementation to the healthy elderly, there may well be clinical circumstances where such supplementation will ultimately prove of significant value.



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