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Aging and Fountain-of-Youth Hormones
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     The search for eternal youth is vibrant in North America. In this search, it is all too easy to ascribe the aging process to endocrines. Although the secretion of growth hormone falls by about 12% per decade after middle age, perhaps the greatest attention has focused on sex steroids, since estrogen secretion falls abruptly in postmenopausal women, and testosterone levels decline with age, though more gradually, in men1,2 (Figure 1A). Levels of the adrenal sex steroid dehydroepiandrosterone (DHEA) and its sulfate ester fall progressively after 30 years of age, and after 60 years of age are less than half the levels in youth (Figure 1B).3

    Figure 1. Changes in Levels of Serum Testosterone in Men (Panel A) and Sulfated DHEA in Both Men and Women (Panel B), According to Age.

    Data in Panel A are from Baulieu,2 and those in Panel B are from Arlt.3

    Association studies have linked all of these age-related changes in hormone levels to some of the phenotypic changes of aging — increased fat mass with visceral adiposity, reduced bone mineral density (BMD) and an increased risk of fracture, sarcopenia and frailty, a decreased quality of life, cognitive impairment, and an increased risk of cardiovascular disease.3 However, association is not causation; efficacy studies require appropriately powered, placebo-controlled clinical trials.

    Recent years have seen a series of high-quality randomized, placebo-controlled trials lasting 6 months to 2 years that have assessed the efficacy of DHEA in older adults. The latest of these trials, a study by Nair et al.4 reported in this issue of the Journal, showed no effect of the administration of DHEA for 2 years (at a dose of 75 mg per day in men and 50 mg per day in women) on body composition, physical performance, or insulin sensitivity, as compared with placebo. Among patients with baseline sulfated DHEA levels that were less than the 15th percentile for normal young women and men — a median value of approximately 0.4 μg per milliliter (1.1 μmol per liter) in women and 0.7 μg per milliliter (1.9 μmol per liter) in men — the levels increased in both sexes by about 3.5 μg per milliliter (9.5 μmol per liter) after treatment with DHEA.

    The results are largely confirmatory. The French DHEAge study, reported in 2000,5 evaluated DHEA (at a dose of 50 mg per day), as compared with placebo, in 280 healthy subjects between the ages of 60 and 79 years. The beneficial effects of treatment were restricted to women and were limited to an increase in libido without improvement in either body composition or muscle strength.6 Muscle power and frailty were specifically addressed in a recent study by Muller et al.,7 which detected no differences between the DHEA group and the placebo group. Reductions in fat-free mass and insulin levels were observed in a 6-month intervention study, but the number of subjects who were studied was small.8

    Positive changes in BMD have been repeatedly observed, but these changes have been small, specific to site and sex, and not reproducible between studies. The DHEAge study demonstrated improvements only in women; these increases in BMD occurred at Ward's triangle in women who were under the age of 70 years and at the radius in those over 70 years.5 The study by Nair et al. showed a slight increase in BMD in the femur in men and in the radius in women. Jankowski et al. reported similar skeletal results after 12 months of therapy in 69 elderly men and women, with a 1.2 to 1.6% increase in BMD at the hip, as compared with that in 71 placebo-treated controls.9 Overall, these inconsistent changes in BMD are approximately half those observed with current osteoporosis therapies, such as estrogen and bisphosphonates, and are unlikely to have a significant effect on the risk of fracture.

    The study by Nair et al. showed that the quality of life of the subjects was unchanged after the administration of DHEA, although, on the basis of the standard deviations in scores on the mental and physical components of the Health Status Questionnaire used in the study, it is likely that the study was not adequately powered to detect clinically meaningful differences in this measure.

    In a parallel component of the overall study, elderly men with total testosterone values below the 15th percentile in a normal young cohort were given transdermal testosterone sufficient to raise their testosterone levels from a median value of 357 ng per deciliter (12 nmol per liter) at baseline to 461 ng per deciliter (16 nmol per liter). Again, no significant functional changes in any of these measures were observed, and increasing evidence suggests that physiologic testosterone replacement should not be given to otherwise normal aging men.1 In the context of a prescribed medication that falls within the guidelines of health care providers and pharmaceutical regulatory networks in most countries, this evidence will be subjected to professional peer review.

    However, another "negative" study on the efficacy of DHEA is unlikely to have much effect on its use in Western societies. Owing to a loophole in U.S. legislation, DHEA is regarded not as a drug but, rather, as a dietary supplement. Although DHEA was never approved as a drug by the Food and Drug Administration (FDA), its status changed from drug to food supplement under the Dietary Supplement Health and Education Act of 1994. Companies that sell supplements may not claim that the products prevent, treat, cure, mitigate, or diagnose disease, but these guidelines are often ignored or circumvented, as appears to be the case with many current providers of DHEA. A search of the keyword "DHEA" on the Internet is most revealing — more than 5 million hits on Google, with many online vendors extolling DHEA as the "foundation of youth," with erroneous and misleading claims. The FDA does occasionally act when supplements are marketed as drugs,10 but, in reality, the FDA has had little impact on this situation. Without a reversal of the current U.S. legislation, DHEA is likely to continue to be used inappropriately, and quackery will prevail. Furthermore, the FDA has no requirements for the composition of supplements. As a result, commercially available DHEA preparations contain from 0 to 150% of the amount stated on the package.11

    Although DHEA and sulfated DHEA are the most abundant steroids secreted from the adrenal cortex, when compared with their corticosteroid counterparts — cortisol and aldosterone — they remain something of an enigma. DHEA is not essential for life (indeed, rodent adrenals do not make DHEA), and the involvement of tissue-specific receptors or intracellular signaling pathways is unclear. Many of the actions of DHEA are thought to be mediated by downstream metabolism within target tissues (such as brain, bone, adipose, and skin) to androgens and estrogens. However, the importance of these pathways is undefined, particularly in men, who have an overwhelming excess of circulating androgens anyway. There is some evidence for the therapeutic use of DHEA in patients with primary or secondary adrenal insufficiency,3 though most studies of this group have focused on improvements in the quality of life.

    Further research focusing on the action of DHEA and its role in patients with DHEA deficiency is certainly indicated. Establishing the hormone's safety or lack thereof might lead to the reclassification of DHEA as a drug, since supplements are defined as causing no harm. To date, the DHEA trials involving elderly patients have shown neither meaningful benefits nor adverse events. Concern has been expressed about the downstream metabolism of DHEA to more potent androgenic metabolites within prostate or mammary glands, but no deleterious changes in prostate-specific antigen or prostate volume have been observed.4,5 However, the report on the Women's Health Initiative study of estrogen replacement in postmenopausal women is a telling reminder that reversing an age-related endocrine deficit may actually cause more harm than good,12 and ongoing vigilance is needed in cohorts of patients with adrenal insufficiency who are prescribed DHEA.

    The search for eternal youth will continue, but the reversal of age-related decreases in the secretion of DHEA and testosterone through "physiologic" replacement regimens offers no answer and should not be attempted. In light of an evidence base for the efficacy of DHEA in patients with adrenal insufficiency, DHEA should no longer be accepted as a food supplement and should instead be treated as a regulated drug. Appropriate regulation would dispel much of the quackery associated with this elusive hormone.

    Dr. Stewart reports having received consulting fees from Duocort, grants from Novo Nordisk and Novartis, and a consulting fee and grant from Pfizer and holding patents on an inhibitor of 11-hydroxysteroid dehydrogenase as a treatment for glaucoma. No other potential conflict of interest relevant to this article was reported.

    Source Information

    From the University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.

    References

    Kaufman JM, Vermulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26:833-876.

    Baulieu EE. Androgens and aging men. Mol Cell Endocrinol 2002;198:41-49.

    Arlt W. Dehydroepiandrosterone and ageing. Best Pract Res Clin Endocrinol Metab 2004;18:363-380.

    Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647-1659.

    Baulieu EE, Thomas G, Legrain S, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A 2000;97:4279-4284.

    Percheron G, Hogrel JY, Denot-Ledunois S, et al. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80-year-old individuals on muscle function and cross-sectional area: a double-blind placebo-controlled trial. Arch Intern Med 2003;163:720-727.

    Muller M, van den Beld AW, van der Schouw YT, Grobbee DE, Lamberts SW. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab (in press).

    Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA 2004;292:2243-2248.

    Jankowski CM, Gozansky WS, Schwartz RS, et al. Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab 2006;91:2986-2993.

    Letter from the Food and Drug Administration to Peter Karpinski, April 9, 2001. (Accessed September 28, 2006, at http://www.fda.gov/cder/warn/cyber/2001/Cyber105.pdf.)

    Parasrampuria J, Schwartz K, Petesch R. Quality control of dehydroepiandrosterone dietary supplement products. JAMA 1998;280:1565-1565.

    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.(Paul M. Stewart, M.D.)