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LE Magazine August 2001

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Below is a detailed summary of recent research findings on DHEA and DHEA-S

DHEA protects the cardiovascular system

Epidemiological studies continue to confirm the correlation between the levels of DHEA in men with their risk of cardiovascular disease. Most recently, the Massachusetts Male Aging Study followed over 1700 men between the ages of 40 and 70 for nine years. The authors found that men in the lowest quartile of serum DHEA at baseline were 60% more likely to develop ischemic heart disease. Low serum DHEA was also a significant predictor. Likewise, studies continue to confirm lower DHEA values in cardiac patients combined with higher insulin levels, with a “close inverse correlation” between insulin and DHEA. This raises the question as to whether DHEA is the “missing link” in hyperinsulinemia and atherosclerosis.

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A very important Canadian study has partly elucidated the way DHEA works to protect blood vessels against atherosclerosis. The authors found that in elderly patients vitamin E is unable to restore the resistance of LDL to oxidation back to the levels found in youth. DHEA, on the other hand, did increase the resistance of LDL to oxidation in a dose-dependent manner. This study found evidence indicating that DHEA is actually incorporated into the molecules of both LDL and HDL cholesterol, and acts as an antioxidant. During aging, however, cholesterol-bound DHEA practically disappears. In the elderly, the levels of cholesterol-bound DHEA are virtually nondetectable, and their LDL cholesterol becomes very susceptible to oxidative damage. (Estrogen esters apparently function in a similar way, protecting LDL against oxidation.)

DHEA has also been shown to reduce the amount of atherosclerotic plaque in rabbits fed a high-cholesterol diet. One clue about the cardioprotective mechanism of DHEA comes from a recent Japanese study, which compared animals given DHEA with animals given DHEA together with an aromatase inhibitor, a compound that prevents the conversion of DHEA to estrogens. The amount of the plaque was diminished by 60% in animals receiving DHEA alone, but only by 30% in animals receiving DHEA and an aromatase inhibitor. The authors conclude that approximately half of the antiatherosclerotic effect of DHEA is due to its conversion to estrogens and an increased release of nitric oxide.

Another study using male castrated cholesterol-fed rabbits as an animal model of atherosclerosis compared the effects of oral DHEA against those of testosterone enanthate given by injection, oral synthetic testosterone and placebo. Sham-operated non-castrated rabbits also served as a control group. Aortic atherosclerosis was highest in the placebo group and lowest in the group receiving testosterone injections. The degree of atherosclerosis was intermediate in the DHEA group, which did better than the oral testosterone group, and slightly better than the noncastrated rabbits that had the benefit of their own testosterone. The study showed that both testosterone and DHEA help prevent atherosclerosis. The benefit could be only partly explained in terms of the impact on the serum lipids.

Finally, a study done at the University of Wroclaw, Poland, found that DHEA decreased the levels of serum lipid peroxides in rabbits fed a normal diet, but not in rabbits with induced severe hypercholesterolemia. However, both healthy rabbits and rabbits with extremely high cholesterol showed an increase in the activity of platelet superoxide dismutase (SOD), a crucial antioxidant enzyme. Again, it should be stressed that this increase in SOD activity was observed both in rabbits fed a normal diet and in rabbits fed an atherogenic diet, which usually show decreased SOD activity. Increase in SOD activity may partly explain DHEA’s antioxidant effects.

Overall, there seems to be a consensus that while DHEA may not be cardioprotective in women, men with low levels of DHEA are at a greater risk of a heart attack. For older men, cardiovascular health appears to be yet another excellent reason for taking DHEA supplements.

Brain protection

DHEA is especially abundant in the human brain. Many earlier studies reported a protective effect of DHEA against the deterioration of mental function with aging, and an inverse correlation between DHEA levels and neurodegerative disease such as Alzheimer’s. A recent Canadian study found that rats implanted with a high dose of DHEA showed significantly less hippocampal damage after stroke was induced (60% injured neurons as compared to 88% for placebo).

In another study, DHEA proved to be the most potent of all the steroids tested in its ability to inhibit the formation of excess reactive astroglia in the event of a penetrating wound of the cerebral cortex, thus downregulating the immune response, which otherwise might injure healthy neurons in the vicinity of the wound. It has been demonstrated that DHEA markedly inhibits tumor necrosis factor alpha (TNF-alpha) and IL-6 in glial cells. The ability to lower the levels of these inflammatory mediators may be an important part of the neuroprotective mechanism of DHEA.

In addition, DHEA has been shown to protect against the toxicity of the amyloid-beta protein and excess glutamate. Treatment with glutamate produced a copious increase in the neuronal glucocorticoid receptor. Treatment with DHEA reversed this increase, demonstrating again the anti-glucocorticoid action of DHEA.

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DHEA is often advertised as a remedy for depression. At this point we know that depression is more than just a shortage of neurotransmitters; it is a whole-body degenerative disease, the most frightening aspect of which is aging-like loss of neural tissue.

DHEA is often advertised as a remedy for depression. At this point we know that depression is more than just a shortage of neurotransmitters; it is a whole-body degenerative disease, the most frightening aspect of which is aging-like loss of neural tissue. There has been a steady interest in DHEA as an antidepressant. First, however, it should be established whether depression is indeed associated with low DHEA. A study done in Cambridge, England, compared DHEA and cortisol levels in clinically depressed patients (categorized as “major depressives”) with a matched group of patients in remission from depression and healthy controls. Both morning and evening levels of DHEA were lowest in depressed patients, with inverse correlation between the morning DHEA levels and the severity of the depression. Evening cortisol levels were highest in the depressed group. The low DHEA/cortisol ratio (similar to the shift seen in aging) also characterized the depressed group. The authors point out that DHEA not only antagonizes harmful effects of excess cortisol, but also may have mood improving properties. This may have “significant implications” for the treatment of depression.

Another study on the role of DHEA deficiency in depression focused on recovering alcoholics, a group especially susceptible to depression, and hence to relapse into drinking. The authors found that abstinent alcoholics showed a deficiency of noradrenaline and a low DHEA to cortisol ratio, indicating lower ability to deal with stress. Hypothetically, DHEA might prove a useful adjunct therapy for recovering alcoholics.

There is still some controversy over whether or not DHEA produces cognitive enhancement in humans. Diamond (1999) has suggested that such enhancement may depend on the degree of psychological stress. In his study on rats, DHEA was found to increase hippocampal activity, but only under non-stressful conditions. Stress appears to block the DHEA-induced enhancement.

The ability of DHEA to protect the hippocampus and enhance its activity is important in regard to Alzheimer’s disease. Studies have generally found increased cortisol and lower DHEA in Alzheimer’s disease patients, together with a low DHEA/cortisol ratio. We know that excess cortisol damages the hippocampus and potentiates beta-amyloid toxicity. DHEA is believed to be able to antagonize the destructive effects of excess cortisol. The authors of a recent study have concluded that dementia is correlated with low DHEA more so than with high cortisol. Another study also showed that while the aging process decreases the DHEA/cortisol ratio, victims of dementia have a significantly lower ratio rather the healthy elderly. Based on the opposite effects of cortisol and DHEA on the brain, especially on the hippocampal region, the authors suggest that it is possible that this pathological imbalance between stress hormones and DHEA accounts for much of the damage.

There has also been some research on the effects of androstenedione, the main metabolite of DHEA, on cognitive enhancement. Androstenedione sulfate has been shown to increase neural activity in certain sections of the rat brain, with implications for memory enhancement and antidepressant action similar to those already found for DHEA.

DHEA’s role in chronic inflammatory diseases

An important overview of the role of DHEA in reducing the damage produced by chronic inflammation was recently published by a team of researchers at the University of Regensburg, Germany. The authors point out that patients with chronic inflammatory diseases such as rheumatoid arthritis show adrenal dysfunction that manifests itself both in insufficient levels of cortisol in response to adrenocorticotropic hormone (ACTH) and low levels of DHEA. With both cortisol and DHEA being too low, the inflammation progresses and leads to harmful consequences.

The current practice is to use synthetic corticosteroids such as prednisolone in an effort to fight chronic inflammation. DHEA remains neglected, in spite of repeated findings of low DHEA levels in patients suffering from chronic inflammatory diseases. But DHEA also plays an important role in preventing inflammation. It is a potent inhibitor of pro-inflammatory cytokines (hormone-like immune chemicals), which in turn signal the immune system and provoke further cellular destruction.

Of special interest is DHEA’s ability to inhibit interleukin 6 (IL-6) and tumor necrosis factor (TNF). These pro-inflammatory cytokines rise with age, and are especially high in patients with inflammatory diseases. IL-6 is known to play a role in promoting bone loss and possibly also joint destruction. In addition, IL-6 promotes the production of certain immune cells which attack the body’s own tissue in autoimmune conditions such as rheumatoid arthritis. High serum IL-6, as seen in rheumatoid arthritis, for instance, is regarded as a reliable biomarker of inflammation. The finding that DHEA supplementation can lower IL-6 makes it a very promising anti-inflammatory agent, especially for chronic disorders which are characterized by significantly elevated IL-6. Besides rheumatoid arthritis, the conditions associated with abnormally high IL-6 include atherosclerosis, osteoporosis, Alzheimer’s disease and certain cancers.

The inverse relationship between DHEA and IL-6 has been confirmed through the study of the menstrual cycle. Serum IL-6 showed a marked rise during the luteal (post-ovulation) phase. This pro-inflammatory cytokine was highest when DHEA levels were lowest, and vice versa.

The primary metabolite of DHEA, androstenedione, has also been found to inhibit the production of IL-6. Likewise, pregnenolone and progesterone also inhibit TNF production.

The deficiency of DHEA in inflammatory diseases also implies a deficiency in peripheral tissue of various sex steroids for which DHEA serves as a precursor. These steroids, both estrogenic and androgenic, are known to have beneficial effects on muscle, bone, blood vessels and so forth. The mainstream therapy with corticosteroids is itself known to lower androgen levels. Consequently, the authors argue that hormone replacement for patients with chronic inflammatory diseases should include not only corticosteroids, but also DHEA.

Other studies also found that adrenal hormones, including DHEA, are of special importance in the treatment of rheumatoid arthritis. There is some evidence pointing to adrenal hypofunction before the onset of rheumatoid arthritis, especially in female patients, who constitute the overwhelming majority of rheumatoid arthritis victims, and whose serum DHEA levels are low (male rheumatoid arthritis patients show low plasma and synovial fluid testosterone). Androgens in general appear to be protective against the development of autoimmune diseases, and DHEA is an important precursor of various androgens. DHEA replacement appears to be especially important for female rheumatoid arthritis patients.

Lupus is another autoimmune inflammatory disease where DHEA (usually in high doses of up to 200 mg) has proven to be a useful adjunct therapy. One author has reviewed the results of all the studies done to date, and concluded that DHEA appears to decrease the requirement for glucocorticoid steroid therapy and somewhat improves symptoms. More important, perhaps, is its protection against bone loss (osteopenia and osteoporosis), as well as improved mental function. Side effects include acne and the lowering of HDL cholesterol (the ratio of HDL to total cholesterol tends to remain the same, however, since LDL cholesterol is also lowered due to DHEA replacement).

Ordinary aches and pains may also be related to low DHEA. When men and women complaining of either lower back pain or neck and shoulder pain were tested, the consistent finding for women was low DHEA and low beta endorphins.


Continued on Page 3 of 4
References on Page 4



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