~DHEA Replacement Therapy

~DHEA Replacement Therapy
Reprinted with permission of Life Extension®.

DHEA is a vitally important hormone. DHEA appears to protect every part of the body against the ravages of aging. In fact, published studies link low levels of DHEA to aging and diseased states.





Youthful hormone balance is critical to maintaining health and preventing disease in men and women over the age of 40. One hormone that is deficient in almost everyone over 35 is DHEA (dehydroepiandrosterone), normally the most abundant steroid in the human body.

A wealth of data indicates that DHEA is a vitally important hormone. DHEA appears to protect every part of the body against the ravages of aging. In fact, published studies link low levels of DHEA to aging and diseased states. Specifically, a deficiency of DHEA has been found to correlate with:

  • Chronic inflammation
  • Immune dysfunction
  • Depression
  • Rheumatoid arthritis
  • Type-II diabetic complications
  • Greater risk for certain cancers
  • Excess body fat
  • Cognitive decline
  • Heart disease in men
  • Osteoporosis


In 1981, the Life Extension Foundation introduced DHEA in an article that described the multiple antiaging effects this hormone might produce.

DHEA did not establish scientific credibility until 1996, when the New York Academy of Sciences published a book entitled DHEA and Aging and summarized the concept of DHEA replacement in their journal Aging (Bellino et al. 1995). These highly technical publications provided scientific validation for the many life extension effects of DHEA replacement therapy. Despite the findings from thousands of peer-reviewed studies, the benefits of DHEA are still not recognized by mainstream medicine. DHEA replacement therapy involves the supplementation of the hormone to restore serum levels to those of a 21-year-old. DHEA is a precursory building block that allows our bodies to more easily create hormones that may be in decline because of age, disease, prescription medications, or other factors. Hormones, such as testosterone and estrogen, as well as serum DHEA levels, begin to decline from 25-30 years of age and may be reduced by 95% of youthful peak levels by age 85.

DHEA Suppresses Inflammatory Cytokines

Chronic inflammation is an epidemic disease of aging. Advancing age results in an increase of inflammatory cytokines (destructive cell-signaling chemicals) that contribute to many degenerative diseases. Rheumatoid arthritis is a classic autoimmune disorder in which excess levels of cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin 1(b) [IL-1(b)], and/or leukotriene B4 (LTB4), are known to cause or contribute to the inflammatory syndrome.

Studies have found that adrenal hormones, including DHEA, are of special importance in the treatment of rheumatoid arthritis (Cutolo 2000). 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.

Chronic inflammation is also involved in diseases as diverse as atherosclerosis, cancer, heart valve dysfunction, diabetes, congestive heart failure, and Alzheimer's disease. In aged people with multiple degenerative diseases, C-reactive protein is often sharply elevated, indicating the presence of an underlying inflammatory disorder. Excess levels of one or more of the inflammatory cytokines [TNF-alpha, IL-6, IL-1 (b), LTB(4)] are usually found when a cytokine blood profile is conducted. DHEA has been shown to lower these pro-inflammatory cytokines and protect against their toxic effects (Kipper-Galperin et al. 1999; Haden et al. 2000).

Thus, DHEA plays an important role in preventing chronic inflammation and also provides signals needed to maintain healthy immune function.

Of special interest is DHEA's ability to inhibit interleukin 6 (IL-6) and tumor necrosis factor (TNF) (Straub et al. 1998; Kipper-Galperin et al. 1999). These proinflammatory 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 (Ferraccioli et al. 1996; Haden et al. 2000). 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 (Wellby et al. 2000). Besides rheumatoid arthritis, the conditions associated with abnormally high IL-6 include atherosclerosis, osteoporosis, Alzheimer's disease, and certain cancers.

The deficiency of DHEA in inflammatory diseases also implies a deficiency in peripheral tissue of various sex hormones for which DHEA serves as a precursor. These hormones, both estrogenic and androgenic, are known to have beneficial effects on muscle, bone, and blood vessels. The mainstream therapy with cortico-steroids is itself known to lower androgen levels. Consequently, the researchers argue that hormone replacement for patients with chronic inflammatory diseases should include not only corticosteroids, but also DHEA (Straub et al. 2000) (see the Inflammation: Chronic protocol for additional supplement recommendations on controlling inflammation).

DHEA as a Virus and Infection Fighter

Some experts think that a state of inflammation is actually required for the activation of HIV (human immunodeficiency virus) and progression to full-blown AIDS (acquired immune deficiency syndrome). If DHEA has potent anti-inflammatory properties, then it should be of great interest to HIV-infected patients because 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 DHEA levels 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. A 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 (Diallo et al. 2000). The mechanism of DHEA's antiviral action is not fully understood, but its antioxidant properties 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 (Christeff et al. 2000). 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.

In addition, DHEA's ability to help the body fight infection (Araghi-Niknam et al. 1998; Oberbeck et al. 2001) 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 because infection increases inflammation (Folsom et al. 2002; Futterman et al. 2002). 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 (Straub et al. 2000; Du et al. 2001). Therefore, DHEA helps the body lower the pathogen load and use its resources to maintain healthy tissue, including a healthy cardiovascular system.

DHEA's AntiAging Properties

DHEA has been shown to improve neurological function (including memory, mood enhancement, and EEG readings), immune surveillance, and stress disorders. DHEA replacement therapy has become popular as an antiaging therapy and offers aging patients help in preventing the ravages of advanced age.

The most remarkable finding about DHEA came from a human study by S.S.C. Yen and associates at the University of California (San Diego), in which 50 mg a day of DHEA over a 6-month period restored youthful serum levels of DHEA in both men and women. Dr. Yen showed that DHEA replacement was associated with an increase in perceived physical and psychological well-being for both men (67%) and women (84%). Increases in lean body mass and muscle strength were reported in men taking 100 mg a day, but this dose appeared to be excessive in women (Morales et al. 1994).

DHEA (50-100 mg a day) was also shown to significantly elevate insulin growth factor (IGF) (Morales et al. 1998). Aging causes a decline in IGF levels that contribute to the loss of lean body mass, as well as to excess fat accumulation, neurological impairment, and age-associated immune dysfunction.

DHEA has been shown to protect against heart disease and atherosclerosis. A study using coronary artery angiography showed that low DHEA levels predispose people to more significant coronary artery blockage (Herrington 1995). Another study showed that DHEA inhibits abnormal blood platelet aggregation, a factor in the development of sudden heart attack and stroke (Jesse et al. 1995). In contrast, some studies on DHEA do not show the cardiovascular disease protection.

In the journal Drugs and Aging, an analysis of studies on DHEA showed that (Watson et al.1996):

  • In both humans and animals, the decline of DHEA production with aging is associated with immune depression, increased risk of several different cancers, loss of sleep, decreased feelings of well-being, and increased mortality.
  • DHEA replacement in aged mice significantly improved immune function to a more youthful state.
  • DHEA replacement has shown a favorable effect on osteoclasts and lymphoid cells, an effect that may delay osteoporosis. (Note: DHEA has been shown in other studies to promote the activity of bone-forming osteoblasts.)
  • Low levels of DHEA inhibit energy metabolism, thus increasing the risk of heart disease and diabetes mellitus.
  • Studies in humans show essentially no toxicity at doses that restore DHEA to youthful levels.
  • DHEA deficiency may expedite the development of some diseases that are common in the elderly.


DHEA and Depression

Depression is a broad term for a host of unpleasant symptoms, including emotional numbness, lack of energy, little motivation, feeling like one is a failure, and feelings of being undesirable. These feelings frequently show up for the first time in middle-aged people who feel like they are "over the hill." Elderly people also frequently become depressed and are particularly at risk of suicide. Depression is a growing problem among teenagers as well.

Physicians have long known that giving estrogen to women and testosterone to men during midlife can avert symptoms of depression, although the effects have never been phenomenal. Reports are stacking up that DHEA works better. DHEA turns into both estrogen and testosterone. (And it just so happens that DHEA decreases about the time people start thinking about being "over the hill.")

DHEA is especially abundant in the human brain. Not only does the brain utilize DHEA, but DHEA is manufactured by the brain. Although researchers do not know what it is supposed to do yet, they do know that giving a person 500 mg of DHEA will cause them to have more REM (rapid eye movement or dream) sleep (Friess et al.1995). This indicates a major role in brain chemistry.

DHEA is the only hormone besides cortisol that has consistently been linked with depression. DHEA was studied as far back as the 1950s as an antidepressant. At that time, researchers reported that it gave people energy and confidence and made them less depressed. Although it seemed to work well, no one followed up on the studies.

DHEA emerged on the scene again in the 1980s when interest in antiaging hormones geared up. It was noted then that antidepressant activity was part of DHEA's overall antiaging benefits. Then, in 1996, a report suggested that DHEA's antidepressant effects might be direct and not just a result of its antiaging benefits in older people. Researchers at Cambridge University discovered that young children with major depression have abnormally low levels of DHEA and abnormally high levels of cortisol (Goodyer et al. 1996).

In the late 1990s, this phenomenon was confirmed in a larger study. Researchers at the University of California at San Diego went back and analyzed old data from a large study that had been done on 699 older women living in Rancho Bernardo, CA. That analysis is the largest study ever done on the association between levels of DHEA and depression. Nine different hormones had been measured during the study that took place during the 1970s and 1980s. Included in the measurements were such things as bioavailable testosterone and sex hormone binding globulin. When the results were in, of all the hormones, only DHEA was associated with depression. Low testosterone levels have been correlated with depression in men (Barrett-Connor et al. 1999).

Women at the lowest end of DHEA were far more likely to be depressed. This coincides with an earlier study in which the percentage of women with depression was 21.7% if they had no detectable DHEA versus 4.6% if DHEA could be detected in their blood. Interestingly, levels of DHEA in the Rancho Study correlate with mood even within the normal range. In other words, the lower the DHEA was, the worse the mood was. And DHEA correlated with mood, irrespective of whether a person was taking antidepressants or not.

A group at the University of California (San Francisco) approached the DHEA/depression question in another way. They decided to give DHEA to people with depression and see if it would help. In the first double-blind, placebo-controlled study on the potential of DHEA as an antidepressant, 11 patients with major depression were given up to 90 mg a day of DHEA for six weeks; 11 were given a placebo. One week before the study actually started, all patients were given a placebo to weed out people who would respond to a sugar pill. The remaining study subjects were then given 30 mg a day of DHEA for the first two weeks; 60 mg for the second two weeks; and 90 mg for the last two weeks. The idea of the graduated dose was to bring patients up to the DHEA levels they had when they were 20-30 years old (DHEA declines with age).

Although the amount of DHEA was not adjusted individually, as it should have been, the graduated dose approximates what it takes to reach a "youthful" level in most people, according to Dr. Owen Wolkowitz, the principle investigator on the study. Some of the participants were taking antidepressants. For these people, the antidepressants were either working partially or not working at all. Only people who had been on the same antidepressant for at least 6 weeks without changing were allowed in the study, and no changes could be made in anyone's medication during the study. After 6 weeks, psychological tests indicated that about half of the participants responded to DHEA therapy, with an overall enhancement of mood scores by 30.5%. This is close to the response rate of antidepressant drugs (Wolko-witz et al. 1999).

An even better response was seen in another study conducted by researchers at the National Institute of Mental Health. In this study, participants were middle-aged people with dysthymia, a chronic, low-grade depression. They were given 90 mg of DHEA a day for three weeks and then 450 mg a day for three weeks more. Batteries of psychological tests were administered, including the Hamilton Depression Rating Scale, the Beck Depression Inventory, a visual analogue scale, and the Cornell Dysthymia Scale. None of the patients were taking any prescription drugs whatsoever except for one man who was taking a hypertension drug. The study was set up in a very rigorous way: all participants received the drug or the placebo for six weeks, and then they were all secretly switched. All people involved in the study were "blind" to who was getting what.

DHEA significantly alleviated the participants' depression. Seven depressive symptoms in particular improved: lack of pleasure, low energy, low motivation, emotional numbness, sadness, inability to cope, and excessive worry. DHEA worked for most people within 10 days. If the supplement was stopped, the symptoms came back. Overall, the response rate was 60% (better than usual results with antidepressants and dysthymia). A DHEA dose of 90 mg a day was sufficient. No extra benefit was provided by the 450-mg dose (Bloch et al. 1999).

Researchers have different theories about how DHEA alleviates depression. Both DHEA and dehydroepiandrosterone sulfate (DHEA-S) can cross the blood-brain barrier and interact with the brain directly. DHEA can affect serotonin, GABA receptors, and other brain factors. One study indicated it might modulate the serotonin-signaling pathway (Inagaki et al. 1999). In addition, DHEA is the precursor for estrogen and testosterone, which have been reported to enhance mood. DHEA also has antistress effects that may be part of its antidepressant action. Research shows that cortisol, the stress hormone, is elevated in major depression. DHEA counteracts cortisol. Calmness appears to be associated with higher levels of DHEA. People who practice transcendental meditation have higher levels of DHEA than those who do not (Glaser et al. 1992). People who took part in a stress-reduction program were able to increase their DHEA by 100%. At the same time, they reduced their stress hormone by 23% (McCraty et al. 1998).

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 (Heinz et al. 1999). Hypothetically, DHEA might prove a useful adjunct therapy for recovering alcoholics.

Exercise has been reported to enhance mood. This mood-enhancing effect may be due to DHEA. Exercise raises levels of DHEA, which also positively affect the heart. In a study in the American Journal of Cardiology , depression and heart attack went together: women with depression are at greater risk of heart attack and vice-versa (Lavie et al. 1999).

DHEA Inhibits Cancer Cell Proliferation

DHEA may be effective in preventing and treating cancer. In one study, DHEA inhibited tumor proliferation of rat liver cells by blocking the cancer cell promoting enzyme glucose 6-phosphate dehydrogenase (G6PDH). The human equivalent dose of 600 mg a day suppressed breast tumors in mice by 70%; yet these scientists showed that even human equivalent doses of 25-120 mg showed striking cancer prevention benefits with no evidence of toxicity (Simile et al. 1995).

DHEA has been shown to inhibit chemically induced cancers in the colon, lung, breast, and skin (Schwartz et al. 1995). When applied directly to the skin, DHEA prevents chemically induced skin cancer (Pashko et al. 1985). DHEA has this effect by blocking the binding of carcinogens to skin cells and by inhibiting the enzyme G6PDH.

One study showed that patients with adult T-cell leukemia (ATL) had significantly decreased levels of DHEA compared to healthy controls (Uozumi et al. 1996). This has led some doctors to speculate that DHEA might be beneficial in treating this form of leukemia because DHEA has already been shown effective in treating hairy cell leukemia. Other cancer studies show DHEA inhibits cancer cell thymidine incorporation needed for cellular propagation and disrupts the oxidizing effects of chemical carcinogens (Schwartz et al. 1986; Hastings et al. 1988; Kim et al. 1999). Scientists point out that DHEA functions not as an antioxidant, but as a modulator of the effects of chemical carcinogens on cells.

DHEA Protects against Brain Aging

Acetylcholine is a neurotransmitter that transmits nerve impulses from one brain cell to another. Acetylcholine is crucial for short-term memory and to protect brain cells against age-associated atrophy. Aging causes a decline in the release of acetylcholine into regions of the brain where it is needed for learning and memory.

In a study published in Brain Research , DHEA was administered to rats in order to measure the effect it produced on acetylcholine release into the hippocampus region of the brain. DHEA significantly increased acetylcholine release above pretreatment levels in all doses tested. At the highest dose, DHEA caused a fourfold increase in the release of acetylcholine compared to the control group. The scientists concluded that this was the first study to demonstrate a direct effect of DHEA in promoting the release of acetylcholine from brain cells in the hippocampus (a critical area for the storage of memory) (Rhodes et al. 1996).

In a study published in Behavioral Brain Research, DHEA interacted with certain neuronal receptors involved in short- and long-term memory storage. The results showed an improvement in memory in the Y-maze spatial learning test that measures short-term memory and the step-down passive avoidance test that measures long-term memory in mice (Maurice et al. 1997).

A study in Life Sciences showed that DHEA could protect against the precursor changes in brain cells that result in the pathological alterations associated with Alzheimer's disease (Danenboerg et al. 1996).

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. It is known 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 study have concluded that dementia is correlated with low DHEA more so than with high cortisol (Murialdo et al. 2000).

DHEA Saves Skin

DHEA has powerful skin protective effects. A study published in the Journal of Surgical Research demonstrates that topically applied DHEA protects the skin's delicate blood vessels. Researchers found that if DHEA were applied after a serious burn, the blood vessels underlying the burned area were protected ( Araneo et al. 1995). Protecting the blood vessels saves the skin. Skin and blood vessels that would otherwise die and peel off can be saved by DHEA. No one knows for sure how DHEA saves skin in this way, but its anti-inflammatory action must have something to do with it. DHEA prevents destructive white blood cells and their biochemical cousins from gearing up. In particular, DHEA affects the blood vessel killer known as tumor necrosis factor (TNF). At the same time it is inhibiting the destructive process, it appears to be prolonging the healing process: DHEA causes edema (swelling) to last longer. This apparently helps save tissue.

Estrogen's skin-enhancing effects are well-known. It provokes collagen and a moisture factor known as hyaluronic acid. Aging decreases both estrogen and collagen. Enzymes that convert DHEA to estrogen also decline. Not surprisingly, women who take synthetic estrogen have scientifically proven thicker skin. Women who take both estrogen and testosterone have really thick skin--48% thicker than women who do not take either hormone ( Brincat et al. 1983). DHEA is converted to both estrogen and testosterone, providing the benefits of both hormones. DHEA is converted into estrogen and androgen-type metabolites found only in skin.

Studies show that DHEA is absorbed by skin when applied topically. A study from CHUL Research Center (in Canada) shows that the skin activity of DHEA applied topically is 85-90% greater than when taken orally (at least in rodents) ( Labrie et al. 1996). No special carriers are needed to get DHEA into skin. A properly formulated topical preparation of DHEA will contain just enough of the hormone to benefit skin without providing enough to escape into circulation. It makes sense to apply the hormones directly to the skin if skin protection is the goal because ingested hormones may end up everywhere but the skin.

DHEA acts against everyday damage as well. By maintaining skin immunity, DHEA preserves the ability of skin to react to cancer-causing, skin-destroying pollutants in air, food, and water (Hastings et al. 1988; Pashko et al. 1992).

Continued . . .


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