REDUCES INFLAMMATION, ENHANCES IMMUNITY, PROTECTS ARTERIES AND THE BRAIN – by Ivy Greenwell – extract from Life Extension magazine

Dehydroepiandrosterone (DHEA) hormones are the most abundant steroids in the human body. Low levels of DHEA are associated with aging and disease states. Specifically, a deficiency of DHEA has been found to correlate with immune dysfunction, inflammation, greater risk of certain cancers, heart disease in men, and osteoporosis. The special interest in DHEA replacement, however, stems from its function as a prohormone, meaning a precursor to a great variety of beneficial steroids, both in the estrogenic and androgenic family, on an “as-needed” basis.

Perhaps the most exciting new finding relates to the antiatherogenic benefits of DHEA. The dramatic aging-related drop in DHEA levels is accompanied by an equally dramatic rise in cardiovascular disease. We have now come closer to elucidating the cardioprotective mechanism of DHEA. It appears that DHEA is incorporated into both high and low-density cholesterol, protecting it from oxidation. In the aged, however, cholesterol-bound DHEA becomes virtually undetectable, and the cholesterol molecules are much more susceptible to oxidation than in young individuals. But this is not the end of the story. It turns out that DHEA also increases the activity of platelet superoxide dismutase (SOD), one of our most important antioxidant enzymes. Thus, DHEA seems to play an essential role as part of the body’s antioxidant defenses.

Another recent finding involves the anti-inflammatory properties of DHEA. It has been known for a long time that DHEA can lower the levels of interleukin-6 (IL-6), a pro-inflammatory cytokine (meaning a chemical messenger used by the immune system) that seriously escalates the inflammatory process, recruiting immune cells that often end up destroying healthy tissue as well. Now it has been established that DHEA can lower the production of another inflammatory cytokine as well, one called tumor necrosis factor alpha (TNF-alpha). The levels of both IL-6 and TNF-alpha rise with aging, showing an increased inflammatory state and possible immune dysfunction. The role of DHEA in regulating the immune response has been shown to include also the enhanced secretion of interferon-gamma. The decline in DHEA levels is closely tied to immunosenescence.

This is excellent news for those who suffer from chronic inflammatory diseases. However, it could be argued that aging itself is, in a sense, a chronic inflammatory state. The levels of various chemical mediators of inflammation, such as IL-6 and TNF, increase as we age. At the same time, our production of DHEA plummets with aging. Maintaining youthful levels of DHEA means less chronic inflammation. It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer’s disease and certain types of cancer.

One surprising finding showed that DHEA can help some infertile patients ovulate and become pregnant, making previously ineffective ovarian stimulation succeed at last.

More good news includes also the finding that DHEA protects brain tissue under conditions simulating stroke and trauma damage, and is likely to be involved in protecting the brain against the development of Alzheimer’s disease. The neuroprotective mechanism of DHEA appears to go beyond its anti-glucocorticoid effect, that is, its ability to antagonize the harmful effects of cortisol; anti-inflammatory action is likely to be involved as well. DHEA has also been shown to lower hyperglycemia (elevated blood sugar) in diabetic rats, and protect their kidneys from the damage caused by high blood sugar. In addition, DHEA enhances the immune response and helps us fight infection; several studies have confirmed its usefulness in combating bacterial, parasitic and viral infections, including HIV. DHEA also helps protect the thymus against cortisol-induced atrophy.

Speaking of cortisol, we are beginning to understand that it is the ratio of DHEA to cortisol that is of critical importance in aging and certain diseases such as AIDS. A recent French study done at the Pasteur Institute in Paris found that the minority of patients who do not succumb to the severe side effects of highly aggressive antiretroviral therapy show a normalized DHEA/cortisol ratio. The majority of AIDS patients, however, have an abnormally low DHEA/cortisol ratio and thus suffer from symptoms usually associated with excess cortisol, even though their cortisol levels are within normal. Cardiac patients and the victims of Alzheimer’s disease also show low DHEA/cortisol ratio. The manipulation of this crucial ratio, including DHEA therapy, could prove highly significant both in the treatment of AIDS and in anti-aging medicine in general. In fact, a small pilot study has already indicated that DHEA combined with an anti-inflammatory drug such as indomethacin can moderate or even normalize the various pathological changes of AIDS-related lipodystrophy.

One surprising finding showed that an 80 mg/day dose of DHEA can help some infertile patients ovulate and become pregnant, making previously ineffective ovarian stimulation succeed at last (in one case, the result was twins!). An animal study confirmed that DHEA is important as a steroidogenic substrate (precursor of other hormones) in ovarian production of various sex steroids. Interestingly, immunomodulatory 7-hydroxy metabolites of DHEA have also been discovered in human semen, with possible further implications for fertility. In postmenopausal women, research on DHEA replacement continues to indicate improved well-being and libido, among many other benefits. We are also closer to understanding the mechanism through which DHEA enhances the sense of well-being: it significantly increases the levels of beta-endorphins.

Those readers who are considering following a ketogenic (low-carbohydrate) diet may be interested in a small study done on rheumatoid arthritis patients: the low-calorie ketogenic diet using less than 40 g of carbohydrates per day resulted in a 34% rise in DHEA within a week; the ketogenic diet was as effective as sub-total fast in raising DHEA levels. This study needs to be replicated, however, using a larger number of healthy subjects. In primates, calorie restriction has indeed been found to preserve higher DHEA levels, indicating a slower rate of aging. In humans, fasting is known to raise DHEA levels in both sexes. Anorexic and bulimic women likewise show higher serum DHEA. Exercise can also raise DHEA in some individuals, possibly due to the inverse relationship between DHEA and insulin. Finally, while meditation has long been known to increase DHEA, participation in drum circles has also been shown to increase DHEA and DHEA/cortisol ratio, confirming the hypothesis that stress reduction in general boosts DHEA production, probably through a shift of adrenal steroidogenesis from cortisol to DHEA. High insulin, high cortisol and low DHEA constitute a large part of the pathological endocrine profile of aging. Restoring the correct hormonal ratios should be one of the primary goals of any anti-aging program.

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, wi
th a “close inverse correlation” between insulin and DHEA. This raises the question as to whether DHEA is the “missing link” in hyperinsulinemia and atherosclerosis.

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.

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.

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