Abstract & Commentary
Synopsis: Administration of 50 mg of DHEA to elderly men and women for 6 months improved insulin action and decreased abdominal fat.
Source: Villareal DT, Holloszy JO. JAMA. 2004;292: 2243-2248.
Abdominal fat increases with advancing age and has been linked to increased risk for diabetes and cardiovascular disease. While insufficient exercise and overeating certainly contribute to age-related acquisition of abdominal fat, hormonal and metabolic factors also have been implicated. Even thin individuals who exercise regularly display increased abdominal fat as they age. This study aimed to determine whether the age-related decline in the adrenal hormone dehydroepiandrosteroine (DHEA) was one of the hormonal factors linked to increased abdominal adiposity and insulin resistance.
Elderly men (n = 28) and women (n = 28) between the ages of 65 to 78 years were enrolled and randomly assigned to receive either placebo or 50 mg of DHEA orally each day for 6 months. The mean body mass index of the men was 28 kg/m2 and that of the women was 27 kg/m2. Those using other hormones and having serious illnesses were excluded. Primary outcome variables were visceral and subcutaneous abdominal fat measured by magnetic resonance imaging and glucose and insulin responses to an oral glucose tolerance test. Ancillary outcome variables included food intake and levels of IGF-1, PSA, estradiol, and testosterone.
DHEA administration raised participants’ serum DHEA-sulfate (DHEAS) into the young physiological range. In women, DHEA use increased testosterone and estradiol, but only estradiol was raised in men. Both groups showed increased IGF-1. SHBG did not change.
Those who used DHEA lost about 2 pounds over the 6 months. Weight loss was similar in men and women. Recorded food intake stayed the same. Both men and women lost abdominal visceral fat, but women lost slightly more than men, 10 vs 7%. Abdominal fat declined 6% in both men and women. Insulin sensitivity improved dramatically and there was an inverse association between changes in insulin sensitivity and visceral fat. There were no adverse events and PSA did not change appreciably in men. Villareal and associates point out that the long-term safety of DHEA use remains unknown. However, based on the outcome variables followed in the study, short-term use appears to positively effect metabolism.
Comment by Sarah L. Berga, MD
Many physiological functions change with age. Adrenal function shows a dramatic ontological pattern that includes both adrenarche during childhood and adrenopause during the senescent years. There can be no doubt that adrenarche causes phenotypic changes. These include growth of axillary and other body hair, increased sebaceous gland secretion, altered body odor, and thickening and pigmentation of the skin. The phenotypic features of adrenopause are less well chronicled, possibly because adrenopause occurs over decades (starting at age 25 years) whereas adrenarche happens over a few years (typically from ages 7-9 years). The results of this study suggest that the increased abdominal adiposity so typical of advancing age is at least partly caused by a decline in the adrenal secretion of the androgenic hormone, DHEA.
The exact mechanisms by which DHEA exerts its impact is still a subject of conjecture, although Villareal et al suggest that DHEA activates the peroxisome proliferator-activated receptor alpha (PPAR), a transcription factor that regulates fatty acid transport proteins that facilitate fatty acid entry into cells and enzymes involved in the oxidation of fatty acids. In other words, DHEA modifies fundamental metabolic pathways in a way that favors fat oxidation and reduces fat deposition.
When these changes occur as part of the tightly orchestrated ontological script that gates the aging process, they are deemed physiological, but that does not necessarily mean they are always desirable. Perhaps we should think of adrenopause as hastening what could be viewed as the "metabolic syndrome of aging." And just as we have medicalized many processes associated with aging, such as osteoporosis, cognitive decline, and menopause, we are now looking to retard other aspects of the aging process by safe and feasible means. I should point out that the "we" in the above sentence does not refer to the medical or pharmaceutical industries, but to the American public.
DHEA, a powerful hormone, is classified as a food supplement for FDA purposes and is sold over the counter. Given that it is a biological agent, it cannot be patented, so there is little pharmaceutical house interest in it. The study does not describe in detail the phenotypic or cosmetic side effects found with DHEA use in this population, but previous studies by other groups have shown that chronic DHEA use can cause androgenic side effects in women, including acne, accelerated balding, or facial hair growth in women. Other studies have suggested that DHEA improves libido, muscle mass, and energy level in those older than age 70 years, but not in perimenopausal women. DHEA can be obtained from many sources, including compounding pharmacies. I would strongly caution against using dessicated bovine adrenal as the source, as this preparation carries the risk of biological contaminants, including prion disease. Of course, medications sold as food supplements are not held to good manufacturing practices, so the quality and uniformity of over-the-counter preparations cannot be guaranteed.
Compounding pharmacies also can prepare a topical preparation. If one administers DHEA, it is best to monitor serum DHEAS levels before and after to ensure that levels are low before instituting therapy and that the levels do not rise above physiological levels after chronic use. Testosterone and estradiol circulate in nanogram and picogram quantities, but DHEAS circulates in the milligram range, so the assays available to monitor levels are robust and reliable. DHEAS has a long half-life and therefore lacks a circadian pattern and can be measured at any time of day.
In summary, DHEA is yet another of the many agents being studied for use in retarding the physiological consequences of aging. Patent opportunities notwithstanding, as the American public grays, there will be increasing demand for nutraceuticals that have promise and appear safe. We can only hope that the hype will be constrained by proactive clinical investigation.
Dr. Berga, Associate Professor, Departments of Obstetrics, Gynecology, Reproductive Sciences, and Psychiatry, University of Pittsburgh, is Associate Editor of OB/GYN Clinical Alert.