I ronically, when I wrote my first major article about DHEA back in 1993, I was depressed. True depression is rarely about anything specific, but if I could have named the cause of my despondency, it would have been the feeling that the total of my efforts did not add up to anything of value. A sense of gloom prevailed. In preparation for the article, I read the lengthy, 24-chapter monograph The Biologic Role of Dehydroepiandrosterone (DHEA), edited by Mohammed Kalimi and William Regelson,¹ while poring over several hundred additional scientific articles. I also cataloged the abstracts of many hundreds more. At first, the project was overwhelming; the subject seemed too difficult to grasp and the conclusions were far from clear. I was a blind man trying to understand an elephant. My normally high levels of energy and high sense of well-being were low. I was in need of DHEA but didn’t know it.

I was determined to learn everything I could about DHEA, and in the process things gradually changed for the better as my knowledge spiraled upward. I started taking DHEA and got over the blues (coincidentally, I thought). As I have continued to study—and consume—DHEA over the interleaving years, the fulfillment of DHEA’s promise is now apparent.

A steroid hormone secreted principally by the zona reticularis of the adrenal cortex, only in humans and related primate species, DHEA is present in far higher concentrations in plasma than any other steroid hormone. Synthesized from pregnenolone (derived from cholesterol), DHEA is rapidly sulfated to yield the ester DHEAS, the predominant form found circulating in the plasma. It can be converted into other hormones, including estrogen and testosterone and has been characterized as a pleiotropic* “buffer hormone,” with receptor sites in the kidney, liver, and testes, where it plays a key role in an extensive range of physiological responses. Production of DHEA starts in puberty and peaks at approximately 20 years, thereafter declining with age, starting at the age of 25. Its decline is progressive and severe, and by the time a person reaches age 75, levels are down by approximately 80% compared to a 20 year old. In what follows, DHEA and its sulfated form, the DHEAS, will be referred to together as DHEA.

* Pleiotropic means producing more than one effect in an organism; especially having multiple observable characteristics or traits.

Longevity and Fat Loss

Some reports correlate DHEA levels to longevity in men.² Studies on laboratory rodents have shown that DHEA treatment reduces total and visceral fat accumulation and protects against development of muscle insulin resistance in response to a high fat diet, with advancing age, and in genetic obesity. As well, relationships have been suggested between lower DHEA levels and heart disease, cancer, obesity, diabetes, chronic fatigue syndrome, AIDS, and Alzheimer’s disease. Additional research implies that autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis might be associated with declining DHEA levels.

To date, there have been well over 1000 clinical trials, with findings that include the following:

Antidepressant Benefits

DHEA was found, in a double-blind, placebo-controlled trial, to provide significant antidepressant benefits for a majority of subjects suffering from major depression.³ Nearly 50% of those given up to 90 mg/day of DHEA for 6 weeks experienced at least 50% improvement in depressive symptoms over the course of the study, with specific improvements in energy, stamina, libido, and sense of well-being. This appeared in 1999, six years after I wrote my first article on DHEA.

Enhanced Sexuality

In a French study led by renowned researcher Étienne-Émile Baulieu, M.D., Ph.D., * 280 men and women supplemented orally with 50 mg of DHEA or placebo daily for a year in a double-blind study. At the end of the study, the female subjects were found to experience a panoply of measurable effects, including the ability to heighten sexuality, with greater enjoyment of physical love in women over 70 years of age.⁴ A significant increase in most libido parameters was also found in these older women.

* In 1960, Professor Baulieu demonstrated that DHEA was the main adrenal androgen, was largely conjugated as a hydrophilic sulfate, and described its metabolism and functions. A fighter in the French Resistance during World War II, among his many accomplishments, Baulieu was director of INSERM (National Institute of Health and Medical Research), and today presides over the Institute of Longevity and Aging (Institut de la longévité et du vieillissement). In 2008, he started the Institut Professor Baulieu to foster research into healthy longevity. These are in keeping with Baulieu’s increasing interest in what he has called the “longevity revolution,” the fact that people are living longer, and its implications. As part of this, he is investigating the potential of hormonal substitution such as DHEA to increase well-being in old age.

Better Bones

Bones under an electron microscope.

Also in the French study, women over the age of 70 taking DHEA were found to have improved bone turnover, increased bone density in various bones, and decreased bone loss. Increased bone loss has been shown to be predictive of hip fracture in women older than 75 years, a particularly bad turn, virtually insuring a rapid decline in health. Thus, it is reasonable to conclude that DHEA can help restore proper bone metabolism.

Improved Skin

Supplementing with DHEA counteracts some of the degenerative processes associated with aging, such as weathered skin.⁵ Unlike certain “moisturizers,” DHEA was found to increase hydration without any indication of harm. Hydration is also associated with increased smoothness of the skin. In the French study cited above, sebum production was increased in all four groups taking DHEA, but most noticeably in the women over 70. Sebum is a fatty substance secreted by the skin’s sebaceous glands. As women age, its production tends to decline. Sebum contains many important protective factors. For example, secretions from the sebaceous glands have recently been found to serve as a major physiologic route of vitamin E delivery to the skin. Also in the French study, DHEA was found to increase epidermal thickness, much as estrogen does.

Schizophrenia Improvement

An Israeli group tested DHEA in a randomized, double-blind, placebo-controlled study, using 27 long-term institutionalized schizophrenic patients (15 men and 12 women, average age 37), all of whom were also taking conventional antipsychotic drugs.⁶

The subjects were given DHEA or placebo orally according to the following schedule: 25 mg/day for the first 2 weeks; 50 mg/day in two equally divided doses for the second 2 weeks; and 100 mg/day in two equally divided doses for the last 2 weeks. As in previous studies with DHEA, these dosages were selected to increase the patients’ circulating DHEA levels to the range of the typical physiological peak in healthy people in their twenties. (After that youthful peak, DHEA levels decline at the rate of about 10% per decade, a loss that may contribute significantly to the aging process. See “DHEA—The Hormone of Youth?” in Life Enhancement, December 2002.)

Using a battery of five standardized tests of mental and behavioral function, the researchers evaluated the patients at baseline (the outset of the study) and every week thereafter for the 6-week duration. They also measured the patients’ blood levels of DHEA. In four of the five tests, the patients receiving DHEA showed significant improvement in negative, depressive, and anxiety symptoms of schizophrenia compared with the patients taking placebo; in the fifth test, the DHEA patients did better than the controls, but the difference was not statistically significant. These results—the first of their kind in a double-blind study—are most encouraging (they’re marred only by some slipshod reporting of the data, which contain internal contradictions).

May Slow Down Aging

Because DHEA is known to peak at high levels in young adults and then decline with increasing age, there has been a high level of interest in using DHEA as an antiaging hormone. A study done in Italy looked for a correlation between DHEA levels and quality of life in people over 90 years of age; the subjects were 36 men aged 90–103 and 39 women aged 90–106.⁷ The study evaluated functional ability and quality of life by dividing the subjects into high-, medium-, and low-functioning groups based on their “activities of daily living” scores. This is a measure of a person’s ability to perform basic daily tasks, such as getting dressed, answering the phone, and maintaining normal hygiene.

The researchers found a direct relationship between DHEA levels and functional independence in men. No such statistically significant result was seen in women, however, leading the authors to suggest that “DHEAS [the sulfate metabolite of DHEA that correlates with DHEA availability] influences different physiological mechanisms in elderly males and females.” This reaffirmed the results of many other studies on DHEA showing marked differences between the sexes in their responses to this hormone.

Improves Arterial Dilation

(click on thumbnail for full sized image) Our arteries are multilayered vessels that need to dilate or contract in response to changing conditions. The chemical signals for these actions are generated in the epithelial cells that line the arterial walls.

A number of past studies have suggested that as DHEA levels decrease, the risk of coronary artery disease increases. But how are these two conditions related? The lack of answers prompted Japanese researchers to recruit 24 men (average age 54) who appeared healthy but who had relatively high cholesterol levels—more than 220 mg/dL (milligrams per deciliter)—for a 12-week clinical trial to observe the effects of DHEA supplementation on their cardiovascular function.⁸ None of the men showed any signs of heart disease or diabetes, and they had normal blood pressure and did not smoke. They were randomly divided into two groups that received a daily dose of either DHEA or placebo. The DHEA dose was 25 mg/day, an amount shown by previous work to restore plasma DHEA levels in this age group to those observed in young adult males.

In several aspects of cardiovascular function—including total cholesterol levels, heart rate, and arterial blood pressure—the researchers observed no change in either the DHEA group or the control group. In the DHEA group, however, two different clinical measurements showed significant improvement in the function of epithelial cells, the cells that line the inner surface of blood vessels and that play a major role in the vessels’ ability to dilate and contract as needed (see above image).

The first measurement was that of flow-mediated vasodilation, which indicates the ability of arteries to dilate when needed in response to epithelial signals. This is important because arteries that do not dilate properly can restrict blood flow throughout the body, a condition that is a good predictor of future cardiovascular problems. In the Japanese study, the measure of arterial dilation that was used more than doubled after 12 weeks of DHEA supplementation, and significant improvements were noted in as little as 4 weeks. Insulin sensitivity was also increased, a very good sign, as too much insulin can be problematic.

Decreased Abdominal Fat

In a preliminary study to test the hypothesis that, as had been found in rodents, DHEA replacement reduces adiposity and improves insulin action, researchers evaluated the effects of six months of DHEA treatment (50 mg/day) in a randomized controlled trial on 56 elderly women and men.⁹ Treatment with DHEA induced significant decreases in abdominal fat and in the insulin area under the oral glucose tolerance curve, without a change in glucose levels, providing evidence for an increase in insulin sensitivity. Also, the researchers found that 6 months of DHEA replacement improved insulin action in elderly individuals.

Treatment for Impaired Glucose Tolerance

A new study, undertaken seven years later by the same primary researchers in the abdominal fat study, set out to determine whether a longer period of DHEA replacement improves both insulin action and glucose tolerance (GT) in elderly women and men.¹⁰ Fifty-seven men and 68 women aged 65 to 75 years were randomly assigned to 50 mg DHEA or placebo once daily for a year in a randomized, double-blind trial. The study continued in the second year, but with an open label protocol. DHEA replacement improved GT in participants who had abnormal GT initially, reduced plasma triglycerides, and the inflammatory cytokines IL6 and TNFα.

DHEA replacement decreases insulin
resistance in individuals with
abnormal glucose tolerance.

Harking back to their previous study, 6 months of DHEA replacement resulted in an improvement in insulin action evidenced by a smaller increase in insulin during an oral glucose tolerance test (OGTT) without a change in glucose response. In the followup study, a longer period of DHEA replacement resulted not only in a reduction in insulin resistance, but also in improved GT, in elderly, overweight or obese women and men with abnormal GT. The magnitude of this improvement was impressive, as DHEA replacement for 1 year resulted in an 18 mg/dl decrease in the 2-hour glucose value of the OGTT and 2 years of DHEA resulted in a 21 mg/dl in the 2-hour glucose value.

DHEA replacement in elderly men
and women improves insulin action.

Treatment for Type 2 Diabetes

These findings have relevance to the current epidemic of impaired GT and type 2 diabetes because they raise the possibility that DHEA could be an effective treatment for impaired GT and for prevention of type 2 diabetes.

In the earlier study, visceral fat, measured by MRI scans, decreased approximately 10% in both men and women. Given the observation that DHEA protects laboratory rodents against visceral fat accumulation and insulin resistance (IR) with aging and in response to high fat diets, the researchers were led to conclude that DHEA improves insulin action, largely by reducing intra-abdominal fat.

However, while the new results confirm that DHEA replacement decreases insulin resistance in individuals with abnormal GT, they do not support the researcher’s previous conclusion that this improvement is largely mediated by a decrease in visceral fat. In the present study, the women had a small increase in fat free mass without a decrease in abdominal fat, while the men had only a small decrease in visceral fat in response to DHEA, suggesting that the reduction in visceral fat observed in the previous 6 month study is a transient effect.

In contrast to the present results, it was recently reported in two studies by Nair, et al.¹¹ and Basu, et al.¹² that two years of DHEA treatment had no effect on insulin action or postprandial glucose turnover in elderly men and women. The difference between the results of that study and the current one, despite a similar study design, would be puzzling were it not for our finding that DHEA replacement improved GT/IR only in those participants who had abnormal glucose tolerance, with no improvement in those with normal GT.

DHEA replacement improved glucose
tolerance/insulin resistance only in
those participants who had abnormal
glucose tolerance, with no
improvement in those with normal
glucose tolerance.

Although the two studies cited above did not perform a standard OGTT, it appears that their subjects were unusually insulin sensitive for their age. Thus, the lack of effect of DHEA on insulin action is consistent with the current finding that DHEA improves insulin action only in individuals with abnormal GT.

DHEA May Reverse Insulin Resistance

Regarding mechanisms by which DHEA may reverse IR, one possibility is by activation of PPARα for which DHEA is a ligand (binder). (See “The Antidiabetes Trigger” in the March 2009 issue.) Activated PPARα stimulates expression of the mitochondrial enzymes involved in fat oxidation and represses activation of enzymes involved in fat synthesis.¹³ Consequently, PPARα activation lowers triglycerides, and could result in less fat deposition in liver and muscle. PPARα activation also suppresses inflammation, and DHEA has been shown to inhibit nuclear factor Kappa B and production of IL-6 and TNFα by various cell types, and to lower circulating levels of these inflammatory cytokines.

Long term usage of modest amounts
of DHEA (50 mg) could become
a first line treatment for
glucose intolerance/insulin resistance
and consequently even
diabetes prevention.

Inflammation May Be the Cause of Insulin Resistance

Chronic inflammation in adipose tissue and macrophages is thought to be one of the factors that mediates IR.¹⁴ In the present study, DHEA replacement resulted in significant reductions in plasma IL-6 and TNFα, suggesting a decrease in inflammation.

The Longer the Better

The results of this study confirm the researcher’s previous finding that DHEA replacement in elderly men and women improves insulin action. Furthermore, these results show that a longer period of DHEA treatment than was evaluated in our previous study (12 months vs. 6 months), also significantly improves GT, and that this improvement occurs only in those individuals who have abnormal GT.

It is entirely possible that long term usage of modest amounts of DHEA (50 mg) could become a first line treatment for GT/IR and consequently even for diabetes prevention in older individuals, not to mention decreasing the increase in chronic inflammation that occurs with aging.

References

1. Kalimi M, Regelson W, eds. The Biologic Role of Dehydroepiandrosterone (DHEA). New York: Walter de Gruyter, 1990.
2. Enomoto M, Adachi H, Fukami A, Furuki K, Satoh A, Otsuka M, Kimagae S, Nanjo Y, Shigetoh Y, Imaizumi T. Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study). J Am Geriatr Soc 2008;56:994-8.
3. Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999 Apr;156(4):646-9.
4. Baulieu ÉÉ, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharrière O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci 2000 Apr 11;97(8):4279-84.
5. Cerimele D, Celleno L, Serri F. Physiological changes in ageing skin. Br J Dermatol 1990 Apr;122 Suppl 35:13-20.
6. Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M, Weizman A. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003 Feb;60:133-41.
7. Ravaglia G, Forti P, Maioli F, et al. The relationship of dehydroepiandrosterone sulfate (DHEAS) to endocrine-metabolic parameters and functional status in the oldest-old. Results from an Italian study on healthy free-living over-ninety-year olds. J Clin Endocrin Metab 1996;81(3):1173-8.
8. Kawano H, Yasue H, Kitagawa A, et al. Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. J Clin Endocrinol Metab 2003;88:3190-5.
9. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: A randomized controlled trial. JAMA 2004;292:2243-8.
10. Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging (Albany NY) 2011 May 10. [Epub ahead of print]
11. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Man CD, Tindall DJ, Melton LJ, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647-59.
12. Basu R, Man CD, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA. Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women. Diabetes 2007;56:753-66.
13. LeFebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPARa in energy metabolism and vascular homeostasis. J Clin Invest 2006;116:571-80.
14. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007;132:2169-80.

Moderator note 2023-02-24: basenote date revised as a side effect of getting this "UnKnown" TYP-vintage thread cross-assigned to a suitable Inner Circle forum.