~DHEA Replacement Therapy, Part 2

~DHEA Replacement Therapy, Part 2
DHEA and Immune Function

DHEA levels decline 80-90% by age 70 or later. DHEA has demonstrated a striking ability to maintain immune system synchronization. Oral supplementation with low doses of DHEA in aged animals restored immunocompetence to a reasonable level within days of administration. DHEA supplementation in aged rodents resulted in almost complete restoration of immune function (Danenberg et al. 1996).

DHEA has been shown in numerous animal studies to boost immune function via several different mechanisms. Only limited human studies have been done to measure DHEA's effect on the immune system.

In one study that focused on men, scientists proposed that the oral administration of DHEA to elderly men would result in activation of their immune system: nine healthy men averaging 63 years of age were treated with a placebo for two weeks followed by 20 weeks of DHEA (50 mg a day). After two weeks on oral DHEA, serum DHEA levels increased by 3-4 times. These levels were sustained throughout the study. Compared to the placebo, DHEA administration resulted in:

  • An increase of 20% in IGF-1. Many people are taking expensive growth hormone injections for the purpose of boosting IGF (insulin-like growth factor) levels. IGF is thought to be responsible for some of the antiaging, anabolic effects that DHEA has produced in previous human studies.
  • An increase of 35% in the number of monocyte immune cells.
  • An increase of 29% in the number of B immune cells and a 62% increase in B-cell activity.
  • A 40% increase in T-cell activity even though the total number of T-cells was not affected.
  • An increase of 50% in interleukin-2.
  • An increase of 22-37% in natural killer cell (NK) numbers and an increase of 45% in NK cell activity.
  • No adverse effects were noted with DHEA administration.


The scientists concluded: "While extended studies are required, our findings suggest potential therapeutic benefits of DHEA in immunodeficient states" (Khorram et al. 1997).

A study published in the Journal of Clinical Endocrine Metabolism showed that when old female mice were treated with DHEA, melatonin, or DHEA and melatonin, splenocytes (macrophages) were significantly higher as compared to young mice. B-cell proliferation in young and in old mice significantly increased. DHEA, melatonin, and DHEA and melatonin helped to regulate immune function in aged female mice by significantly increasing the cytokines interleukin-2 and interferon-gamma and significantly decreasing the cytokines interleukin-6 and interleukin-10, thus regulating cytokine production (Inserra et al. 1998).

Interleukin-6 (IL-6) is one of the pathogenic elements in inflammatory and age-related diseases, such as rheumatoid arthritis, osteoporosis, atherosclerosis, and late-onset B-cell neoplasia. According to a report in the June 1999 issue of the Journal of the American Geriatrics Society , "higher circulating levels of IL-6 predict disability onset in older persons." The authors suggest that IL-6 may cause a reduction in muscle strength or contribute to specific diseases such as congestive heart failure, osteoporosis, arthritis, and dementia, which cause disability (Ferrucci et al. 1999).

DHEA has consistently been shown to boost beneficial interleukin-2 and suppress damaging interleukin-6 (IL-6) levels. Interleukin-6 is overproduced in the aged, which contributes to autoimmune disease, immune dysfunction, osteoporosis, depressions in healing, breast cancer, B-cell lymphoma, and anemia. Continuous DHEA administration maintained immunocompetence in aged animals (by boosting interleukin-2 and other beneficial immune components and suppressing interleukin-6 and other detrimental immune components). Suppression of interleukin-6 with 200 mg a day of DHEA was shown to be effective against systemic lupus erythematosus (Van Vollenhoven et al. 1998).

Researchers compared levels of IL-6 in 283 subjects with a mobility or functional disability with IL-6 levels in 350 adults without a disability. The investigators found that adults in the highest third of values of IL-6 had a 76% higher rate for mobility disabilities and a 62% higher rate for inability to perform daily activities than subjects in the lowest third of values. "These data suggest that IL-6 is a global marker of impending deterioration in health status in older adults," wrote a team led by Dr. Luigi Ferrucci at the National Institute on Aging in Bethesda, MD (Ferrucci et al. 1999).

In a study in the Proceedings of the Society for Experimental Biology and Medicine, DHEA has been shown to restore normal cytokine production in immune system dysfunction induced by aging by suppressing the excessive production of cytokines (IL-6) by 75%, although increasing IL-2 secretion by nearly 50%, during a leukemia virus infection in old mice (Inserra et al. 1998).

Another study in normal healthy individuals over the age of 40 found an opposite relationship between plasma DHEA levels and the presence of detectable levels of IL-6. Studies also revealed that low doses of DHEA and DHEA-S inhibited the production of IL-6 in unstimulated human spleen cell suspension cultures and enhanced its release by cultures transferred from organs of the same tissue (James et al. 1997).

The age-related increase in circulating IL-6 levels in humans, which has been attributed to decline in DHEA production by the adrenal gland, is currently attracting attention because of its possible relevance to the etiology and management of a number of age-related clinical disorders. The potential importance of these observations and suggestions has prompted us to perform more detailed studies on the relationship between IL-6 and DHEA. Using immunoassay techniques, scientists found in normal healthy individuals over the age of 40 that low levels of plasma DHEA levels predicted levels of IL-6 (James et al. 1997).

DHEA for Postmenopausal Women

The importance of DHEA, a precursor of estrogen and testosterone, in psychological and sexual health has been underlined in a number of studies. For example, a German study found that DHEA-deficient women supplementing with 50 mg of DHEA daily for four months had decreased symptoms of depression and anxiety and improved libido (Arlt et al. 1999).

A study by an Italian team of investigators suggests that DHEA may be an effective option for preserving health in postmenopausal women. The study concluded that oral administration of 50 mg of DHEA daily for six months mimics the benefits of traditional hormone replacement therapy (HRT), namely, estrogen-progestin in terms of its effects on the GHRH-GH-IGF-1 (growth hormone-releasing) axis (Genazzani et al. 2001). The axis oversees the control of several endocrine functions, including the stimulation of osteoblasts (bone cells) to stimulate skeletal growth in children and maintain bone integrity in adults. During menopause, however, the drop in estrogenic activity reduces the secretion of the hormones of this axis and slowly the bone reduces the amount of calcium and osteoporosis begins.

The study by the Italian team involved 31 postmenopausal women, who were divided according to their age into two groups (50-55 and 60-65 years). They were tested for hormonal levels at three months and then six months of therapy and were subjected to a GHRH test before and after the study. Researchers measured the effects of DHEA with ultrasound and bone mass density (BMD) examinations before and after the study. Results showed that the levels of all DHEA-derived steroids and osteocalcin, as well as GH and IGF-1, were increased in plasma under DHEA supplementation (Genazzani et al. 2001).

DHEA Dosing and Safety Precautions

Properly managed DHEA therapy can be useful for most older men and women to increase energy, vitality, and foster an overall youthful feeling. However, there are guidelines that should be followed for safe long-term use of DHEA.

When taking oral supplements of DHEA, it is important that antioxidants are available to the liver because DHEA can promote free radicals in liver cells. Animal studies have shown that extremely high doses (from 2000-10,000 mg DHEA daily in human terms) caused liver damage in mice and rats (Metzger et al. 1995). When antioxidants were given along with the DHEA, liver damage did not occur despite the massive doses of DHEA being administered to these animals (Swierczynski et al. 1997). It should be noted that the amount of DHEA shown to cause liver damage is 20 times more than is necessary to produce antiaging benefits. Green tea, vitamin E, and N-acetyl-cysteine (NAC) are antioxidants that have been shown to be especially effective in suppressing free radicals in the liver.

The Life Extension Foundation has evaluated thousands of DHEA blood tests to determine the ideal dose of DHEA for both men and women. The Foundation's findings indicate that the optimal dosage range for DHEA varies considerably between individuals. Prior recommendations to take DHEA 3 times a day are now being replaced with a general recommendation that men and women should consider taking between 15-75 mg a day in 1 morning dose. Most human studies use one daily dose of 50 mg, and this is the typical daily dose that the majority of people use to restore serum DHEA to youthful levels. DHEA can be taken with or without food, although some believe that fat helps DHEA to assimilate better. Some people absorb DHEA better by taking it 20-30 minutes before meals.

A DHEA-S blood test should be taken 3-6 weeks after beginning DHEA therapy to help determine optimal dosing. Some people neglect to test their blood levels of DHEA and wind up chronically taking the wrong dose. When having your blood tested for DHEA, blood should be drawn 3-4 hours after the last dose. DHEA testing can save you money if testing shows that less DHEA can be taken to maintain youthful DHEA serum levels.

The standard blood test to evaluate DHEA status is one that measures DHEA-S. The DHEA-S is calculated in micrograms per deciliter (mcg/dL) of blood. The youthful ranges of DHEA are as follows:

Men: 400-560
Women: 350-430

People over age 40 who do not supplement with DHEA usually have serum levels below 200 and many are below 100. Chronic DHEA deficiency is a risk factor for developing the degenerative diseases of aging according to the preponderance of evidence existing in the scientific literature.

Some people obtain a baseline DHEA-S blood test before beginning DHEA replacement therapy. However, based upon numerous DHEA blood tests evaluated by the Life Extension Foundation, anyone over age 40 who does not supplement DHEA is already deficient in serum DHEA. Therefore, it may be more economical to have the first DHEA blood test 3-6 weeks after initiating DHEA replacement therapy. There are precautions that should be observed that are different for men and women.

DHEA Precautions for Men

Before initiating DHEA therapy, men should know their serum PSA (prostate-specific antigen) level and have passed a digital rectal exam. Men with prostate cancer or severe benign prostate disease are advised to avoid DHEA because DHEA can be converted into testosterone (and estrogen). These sex hormones and their metabolites can promote benign and malignant prostate cell proliferation. It is important to understand, however, that well-controlled studies show that serum DHEA levels are usually lower in men with malignant prostate disease compared to healthy control subjects. Therefore, men are advised to have a PSA and digital rectal exam before initiating DHEA therapy to rule out existing prostate disease, not because DHEA causes the disease. On the contrary, there is evidence indicating that maintaining youthful levels of DHEA may protect against prostate cancer. To reduce the risk that hormone modulation with DHEA could contribute to a prostate problem, men taking DHEA are also advised to take:

  • Vitamin E - 400-800 UI a day
  • Selenium - 200-400 mcg a day
  • Gamma E Tocopherol - 200 mg a day
  • Lycopene Extract - 20-40 mg a day
  • Saw Palmetto Extract - 160 mg 2 times a day
  • Pygeum Extract - 50 mg 2 times a day
  • Nettle Extract - 120 mg 2 times a day


Aging men often have high levels of estrogen (estradiol) and dihydrotestosterone (DHT). If a blood test reveals estradiol levels above 30 (pg/mL), an aromatase inhibitor should be taken. This can either be in the form of a prescription drug, such as Arimidex (0.5 mg taken twice a week), or a dietary supplement called Super Mira Forte (6 capsules a day). If serum DHT levels are too high, taking 5 mg a day of the prescription drug Proscar can lower them to safe ranges.

Men over 40 should consider checking their PSA and DHEA-S serum levels every 6-12 months thereafter. Men should also periodically check their blood levels of free testosterone and estrogen to make sure that DHEA is following a youthful metabolic pathway. Men taking DHEA should refer to the Male Hormone Modulation protocol to learn about additional hormone balance testing that can be done at the same time serum DHEA and PSA levels are being tested.

DHEA Precautions for Women

DHEA can increase serum estrogen levels in women and eliminate the need for estrogen replacement therapy in some women. To help protect cells (especially breast cells) from excessive proliferation in response to estrogen, women taking DHEA should also take:

  • Melatonin - 300 mcg-3 mg every night
  • Vitamin E - 400-800 IU a day
  • Gamma E Tocopherol - 200 mg a day
  • Indole-3-carbinol - 200 mg twice a day
  • Vitamin D3 - 1000-1400 IU a day


Women should consider estrogen and free testosterone testing when they take their DHEA blood test in order to evaluate DHEA's effect on their blood levels of estrogens.

Women who have been diagnosed with an estrogen-dependent cancer should consult their physicians before beginning DHEA therapy. Some studies indicate that higher serum DHEA protects against breast cancer, but no adequate studies have been done to evaluate the effects of DHEA in breast cancer patients. If DHEA were to elevate estrogen too much, this could theoretically increase the risk of breast cancer. Women taking DHEA should refer to the Female Hormone Replacement protocol for information about restoring complete youthful hormone balance.

Liver Disease

Men or women with existing liver disease (such as viral hepatitis or cirrhosis) should consider taking DHEA sublingually (under your tongue) or using a topical DHEA cream to reduce the amount of DHEA entering the liver. DHEA is converted by the liver into DHEA-S. Those with liver disease should carefully monitor liver enzyme levels to be certain that DHEA therapy is not making existing liver disease worse.

DHEA is best taken early in the day or possible insomnia could result. DHEA is normally produced by the adrenal glands early in the day and then converted by the liver to DHEA-S by midday when the DHEA/DHEA-S ratio is usually stabilized (10% DHEA/90% DHEA-S).

We again recommend that those already taking DHEA should have a DHEA blood test to make sure they are taking the precise dose to suit their individual biochemistry.

Some people only need to take a small amount of DHEA to restore blood levels to that of a 21-year-old, although others need to take higher levels of DHEA. Those with existing prostate or breast cancers should not take DHEA unless closely supervised by a knowledgeable physician who understands DHEA's metabolic pathways.

Some people supplement with the hormone pregnenolone in lieu of or in addition to DHEA. Because pregnenolone naturally converts into many of the same hormones as DHEA, some of the precautions we advise for DHEA may apply to pregnenolone.

DHEA tests often cost more than $100 at local laboratories, but the Life Extension Foundation offers low-cost DHEA-S and PSA (prostate-specific antigen) testing to members by mail order. For complete information about the availability of discount blood testing in your area, refer to the Medical Testing protocol or call (800) 208-3444.

If DHEA replacement sounds complicated, it is, compared to other preventive supplement programs. We suggest weighing the documented antiaging benefits of maintaining youthful serum DHEA levels when deciding whether to embark on a DHEA replacement regimen, or stated differently, review the degenerative effects of chronic DHEA deficiency to decide whether this program is worth your time and money.


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