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Life Extension Magazine

LE Magazine August 2001

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Adrenal hypofunction replacement

Addison’s disease is another chronic condition that results from the dysfunction of the adrenals. Addison’s patients are given corticosteroids and mineralocorticoids to compensate for their low adrenal production of these vital hormones, but so far the need to raise their abnormally low DHEA levels has not been addressed by the mainstream medical establishment. A much-needed double-blind, placebo-controlled study has finally investigated the effects of 50 mg of oral DHEA on male and female patients suffering from Addison’s disease. As a result of DHEA replacement, the levels of DHEA and androstenedione reached physiological levels in both sexes. In women, the effect of DHEA included a rise in total testosterone to low-normal levels and a decrease in serum sex hormone-binding globulin (this leads to greater bioavailability of all sex hormones). Both sexes showed an improvement in self-esteem and overall well-being, with less fatigue. The authors point out that the psychological improvement in male Addison’s patients indicates that the action of DHEA on the brain may be independent of the levels of testosterone.

DHEA helps fight bacteria and viruses, including HIV

An infection with human immunodeficiency virus (HIV-1) typically does not result in full-blown AIDS except after a period of latency. Certain factors have to activate the virus. These factors include antigens, mitogens and cytokines such as tumor necrosis factor alpha (TNF-alpha). Some experts think that a state of inflammation is actually required for the activation of HIV and progression to full-blown AIDS. If DHEA has potent anti-inflammatory properties, then it should be of great interest to HIV-infected patients, since high levels of DHEA might help prevent the activation of the virus. Even if based on only partial evidence, the advice that HIV patients should maintain their DHEA as high as possible appears to be sound.

Indeed, it has been shown that DHEA and its synthetic analogs are able to produce partial inhibition of HIV replication. One study discovered that one particular analog of DHEA, IM28, had a somewhat higher activity against HIV replication than DHEA, but at a price: it was more toxic than DHEA. The mechanism of DHEA’s anti-viral action is not fully understood, but its antioxidant properties (perhaps deriving from the estrogenic metabolites) and its impact on metabolic enzymes are probably part of the explanation.

Another important aspect involves the close relationship between DHEA, cortisol and the types of cytokines produced. As AIDS progresses, we see a deficiency of type I cytokines (including interferon gamma and interleukin-2) and an excess of type II cytokines, including interleukin-6 (IL-6). This is accompanied by a rise in cortisol and a drop in DHEA levels. Effective therapy with protease inhibitors has been shown to increase DHEA levels.

HIV is not the only virus that can be inhibited by DHEA. An interesting study conducted at the University of Tucson in Arizona investigated the effect of DHEA and melatonin on the immune function and tissue vitamin E levels in healthy mice and mice infected with leukemia retrovirus, which leads to murine (mouse) acquired immune-deficiency syndrome (AIDS). The retrovirus causes a loss of tissue vitamin E, a decrease in T helper 1 (Th1) cytokines and an increase in T helper 2 (Th2) cytokines, as well as a reduction in B and T cell count. Both DHEA and melatonin prevented the drop in B and T cell proliferation, and the increase in Th2 cytokines. When melatonin and DHEA were used together, however, they were more effective. When administered simultaneously, DHEA and melatonin were also able to prevent vitamin E loss and reduce lipid peroxidation in the liver. Supplementing these two hormones also increased tissue vitamin E levels in healthy mouse. The results suggest that the combined treatment with DHEA and melatonin may be of use as adjunct therapy against retroviral infection.

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In addition, DHEA's ability to help the body fight infection and infection-caused inflammation may be a part of its cardioprotective mechanism.

Another interesting study to explore the combined use of DHEA and melatonin has been done in Korea. It studied the effects of DHEA, melatonin, and the combination of DHEA and melatonin on the release of tumor necrosis factor alpha (TNF-alpha) by mouse macrophages in the presence of the anthrax toxin, which is produced by the anthrax bacteria. The release of inflammatory cytokines, such TNF-alpha, is known to play a central role in the development of anthrax. The authors found that DHEA markedly inhibited the anthrax toxin-induced production of TNF-alpha; melatonin was also effective. Combining DHEA with melatonin, however, worked no better than single therapies.

Another study investigating the protective effects of DHEA against the damage of bacterial sepsis (a condition that sets in as a wound becomes infected) was done at the University of Essen, Germany. Untreated mice with sepsis had a survival rate of 53% after 48 hours; a group of mice that received DHEA had an 87% survival rate. The authors found that the immunoenhancing effect of DHEA is associated with lower release of TNF-alpha and greater activity of T cells. Previous animal studies have also indicated that DHEA significantly improves bacterial killing due to sepsis associated with thermal injury. Trauma with ensuing sepsis is a leading cause of death in young people; the possibility that DHEA might be a helpful adjunct therapy for male trauma patients is being studied.

DHEA has long been known to boost the immune function. It is vital for the development of certain mature immune cells and for enhanced antibody production. A new study has found that the number of cells secreting interferon-gamma correlated with serum DHEA levels in men, and that the activity of these cells was associated with DHEA levels in premenopausal women. Thus, DHEA seems to be involved in modulating cytokine production. The same is true of one of its metabolites, androstenediol, which has been shown to protect bone marrow function and resistance to infection after exposure to radiation in rodents even more effectively than DHEA. Androstenediol has also been shown to protect against lethal infection with influenza A virus. Because infection produces a rise in cortisol, which in turn suppresses the immune system, it would be logical to try to counterregulate this immunosuppression with antiglucocorticoids such as DHEA.

In HIV patients, interferon gamma levels have been found to be significantly positively correlated with DHEA levels. Low DHEA, on the other hand, correlates with viral load and is a predictor of poor prognosis. One interesting finding has been that protease inhibitor therapy may help restore higher DHEA levels.

Since cortisol and DHEA partly control both metabolism and the immune response, one recent study compared cortisol/DHEA ratio in healthy controls with that found in HIV-infected patients receiving different types of therapy. The findings were dramatic. First, it needs to be stated that an alarming 63% of AIDS patients receiving highly aggressive antiretroviral therapy develop lipodystrophy. Lipodystrophy is a lipid disorder characterized by accumulation of fat on the abdomen and neck and back (dorsocervical fat), high cholesterol, apolipoprotein and triglycerides, increased risk of diabetes or actual diabetes, cardiovascular disease, fragile bones and muscle loss. These patients showed low levels of DHEA and a low DHEA/cortisol ratio.

The pathological changes of lipodystrophy are typical of those induced by excess cortisol. A recent study showed that cortisol levels in HIV patients are actually within the normal range; it is the deficiency of DHEA that results in relative hypercortisolism. Those lucky patients who do not succumb to lipodystrophy, on the other hand, have been found to have considerably higher DHEA levels and a normalized DHEA/cortisol ratio. The patients with normal DHEA/cortisol ratio also have much better T cell counts. Obviously, DHEA/cortisol ratio is critical in this disease; restoration and maintenance of a normal DHEA/cortisol ratio should be one of the important goals of any AIDS treatment. (Considering how many elderly also show lipodystrophy, even though milder than that induced by retroviral drugs, it could well be argued that the maintenance of a normal DHEA/cortisol ratio should be a crucial part of any anti-aging regimen).

Fortunately, we now have the findings of a small study that used DHEA supplements in an attempt to combat lipodystrophy in HIV patients. Seven patients with lipodystrophy, three of whom had developed diabetes, were given 100 to 200 mg/day of DHEA and an anti-inflammatory drug (indomethacin or naprosyn). DHEA alone led to better blood sugar and lower serum lipids. The addition of an anti-inflammatory led to a further improvement in blood sugar and visible decrease in dorsocervical fat.

One of the markers of increasing immune dysfunction related to aging is the progressive atrophy of the thymus gland. DHEA and its metabolite 7alpha-hydroxy-DHEA have been shown to protect the thymus against atrophy induced by the stress hormones (glucocorticoids). A French study found that if either DHEA or its 7alpha-hydroxy metabolite were added to the in-vitro culture of thymocytes before its treatment with dexamethasone (a synthetic cortisol-like hormone), there was much less apoptosis (programmed cell death) of thymic epithelial cells. Thymus atrophy plays a part in the general immunosenescence that some scientists consider one of the most destructive mechanisms driving aging. The antiapoptotic action of DHEA in the thymus is thus of major importance for the preservation of immune competence.

In addition, DHEA’s ability to help the body fight infection and infection-caused inflammation may be a part of its cardioprotective mechanism. Many holistic experts believe that infection is a significant causal factor in atherosclerosis, since infection increases inflammation. Part of the cardioprotective role of DHEA may stem from its ability to thwart viruses by inhibiting free radical generation and NF kappa B activation, thus reducing inflammation and viral replication. Thus, DHEA helps the body lower the pathogen load and use its resources to maintain healthy tissue, including a healthy cardiovascular system.


References on Page 4 of 4


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