DHEA: Happy 120th Birthday??

Not all of the hormones produced in our bodies decline with aging.



Estrogen, made by the ovaries, declines dramatically only after menopause. Melatonin, made by the pineal gland, declines progressively as the decades march on. DHEA and DHEAS, made by the adrenal glands, also progressively drop with aging starting in our late 20’s. However, other steroids made by the adrenal glands, such as cortisol and aldosterone, stay relatively stable throughout life. Furthermore, the amount of androgens produced by the testicles drops only slightly with aging.



A number of changes occur in our bodies as we age. There’s a substantial reduction in protein synthesis leading to shrinkage in muscle mass, and decreased bone formation leading to osteoporosis. Many researchers think that these changes are closely related to the age-associated decline in hormones. Some even think that restoring these declining hormones could 1) delay muscle wasting, 2) strengthen bones, 3) maintain a healthy heart, and 4) slow the progression of aging..



From Infancy to 120–DHEA throughout life

The pattern of DHEA(S) production by the human body is interesting. Although a fetus makes DHEA(S), and this hormone is present in a baby for the first few months of life, there is very little made from 6 months up to the beginnings of puberty. From then on the levels continually rise and peak in our 20’s. From our 30’s on, there is a progressive decline in DHEA(S) levels (Orentreich, 1984). It is estimated that by age 70 we only make a fourth of the amounts made in our prime, and by age 90, perhaps a tenth (Migeon, 1957, Birkenhager-Gillesse, 1994, Ravaglia, 1996). One study has found that there is a 60% decrease in DHEA and DHEAS between ages of 40 and 80, alone! (Belanger, 1994).



Since DHEA is the precursor to androgens and estrogens, the decline in DHEA production also reflects itself in the cells of our bodies. It is thought that at least half of the androgen and estrogen precursors in our body comes from DHEA. The rest are made from the testicles and ovaries.



After menopause, when the ovaries are practically no longer functioning, 100% of the estrogen precursors comes from the adrenal glands’ DHEA (Labrie, 1991).


From mice to men, and women

Most of the longevity studies showing increased lifespan with DHEA have been done on rodents (Lucas, 1985). Although the majority of these studies confirm a lifespan-extending effect with DHEA, we should keep in mind that, unlike humans, rodents have little circulating DHEA(S) in their blood (Nestler, 1995). This, alone, should caution us about jumping to conclusions based on results of animal studies. This was emphasized by Dr. Peter Hornsby, from Baylor College of Medicine in Houston, Texas, when he wrote, “Although experiments in rodents on the effects of DHEA have been extremely valuable, we should always bear in mind the difficulty in applying rodent data to humans… In rodents, tissues may respond to DHEA quite differently since they do not normally have high levels of DHEA in their plasma.”



Countless rodent studies have been done with DHEA that have shown increased lifespan and positive influences on a variety of illnesses such as heart disease, diabetes, and cancer. I have purposely chosen not to focus on these studies because conclusions from these studies extraploted to humans could be misleading and inaccurate. As much as possible, human studies have been emphasized in this book.


A group of human volunteers get DHEA

Drs. Morales, Nelson, Nolan and Yen, from the Department of Reproductive Medicine, University of California School of Medicine, San Diego, (in La Jolla), wanted to find out the influence of DHEA supplements on middle-aged and older individuals. (We briefly mentioned this 1994 study in Chapter 1.) They were aware that aging is associated with a gradual shift from a ‘young’ state characterized by the building-up of muscles and tissues, called anabolism, to an ‘aged’ state characterized by the loss of muscle mass and strength, called catabolism (not to be confused with cannibalism).



These researchers recruited 13 men and 17 women who ranged from 40 to 70 years of age. Using a randomized, placebo-controlled, cross-over trial (the best careful and meticulously designed study for human research), they provided 50 mg of DHEA nightly for 3 months. During the study period they measured blood levels of many hormones and nutrients including androgens, lipids, and insulin, as well as body fat, libido, and sense of well-being. Within two weeks of treatment, the DHEAS levels in the bloodstreams reached those found in young adults.



A striking finding became apparent. The researchers state: “DHEA supplementation resulted in a remarkable increase in perceived physical and psychological well-being for both men and women. The subjects reported increased energy, deeper sleep, improved mood, more relaxed feeling, and an improved ability to deal with stressful situations.”



Interestingly, no changes were noted in libido or body fat. Changes in blood lipids levels such as cholesterol were not significant.



Based mostly on results of this relatively short-term study, a number of people started DHEA supplements and a lot of media hype was generated. Articles appeared in various newspapers and magazines. Even Newsweek’s August 7, 1995 article on melatonin had a sidebar titled, “Nature’s Other Time-Stopper?”



In order to find out whether higher doses and a longer period of treatment would have a more significant effect, Drs. Yen, Morales, and Khorram (1995) gave 100 mg of DHEA to 8 men and 8 women between the ages of 50 and 65 for 6 months– twice as long as the earlier study.



With 100 mg of DHEA on board, the serum levels of DHEAS increased several-fold in both men and women. The androgen levels doubled in the men, and quadrupled in the women. One of the eight women developed facial hair that resolved by the end of the study.



There were many biological markers assessed throughout the study. Lean body mass showed an increase in both genders, there was some increase in muscle strength of the knee, and no change was found in lipid profiles, insulin or glucose levels, nitrogen balance, bone mineral density, or basal metabolic rate. Interestingly, there was no mention of DHEA’s effect on well-being as had been reported in the earlier study of 3 months.


Here are some theoretical mechanisms on how supplemental DHEA can increase lifespan, remembering, though, that as of yet there is no proof that it does so in humans:



  • Improving Immunity

  • Turning on “youth” genes in our DNA that may be shut off by low levels of DHEA in old age

  • Decreasing rate of heart disease by lowering cholesterol and acting as a blood thinner

  • Decreasing the rate of cancer


  • Improving insulin’s function thus better regulating blood sugar levels

  • Balancing DHEA/cortisol ratios. As we age DHEA levels drop but cortisol levels stay relatively the same. This unbalanced ratio may have harmful consequences on blood sugar, immunity, among others.

  • Inhibition of glucose-6-phosphate dehydrogenase enzyme. This enzyme is involved in cancer promotion, lipid formation and production of toxic oxygen free radicals

  • Enhancing mood and energy. Enhanced well-being could have a mind-body effect on improving our health.

    Do DHEA supplements have a role in hormonal replacement therapy and influence longevity?

    I asked the opinions of the world’s top researchers:

    Michael Bennett, M.D., from the Department of Pathology at the University of Texas, Southwestern Medical Center in Dallas, has been researching DHEA for 9 years, especially its effects on the immune system of rodents.

    DHEA does not have the bad effects that androgenic steroids, such as those used by some body builders, have. It is a precursor to estrogen which can possibly lead to breast enlargement in men if used in high doses. In women, high doses could pose the risk of an overabundance in androgens leading to such side effects as hirsutism (excess body hair). Many strains of mice have lived longer when supplemented with this steroid.



    I’m 60 years of age. If my blood test showed that my level was low, I would consider taking low doses such as 25 mg to bring my levels higher. However, I would prefer being part of an experiment to test the effects of low-dose DHEA.


    Etienne-Emile Baulieu, M.D., Ph.D., Director of the Institut National de la Sante et de la Recherche Medicale (similar to the US NIH), Department of hormone research, Paris, France.

    This is my favorite theory. We are studying the possible beneficial effects of re-establishing a “young” level of DHEAS in people over 60 years of age. The comparison to estrogen replacement therapy after menopause is a good one.



    However, we need long-term studies to make sure that there are no negative effects on hormone responsive tumors such as prostate and breast. We are currently doing studies on DHEA’s role in cerebral function, cardiovascular system, bones, muscles, skin, metabolic (lipids, glucose) and hormonal (pituitary, insulin) parameters. We expect important influences by DHEA on most of these functions.



    I would consider taking 25 mg or 50 mg daily if my blood levels were found to be low.


    Peter J. Hornsby, Ph.D., from the Huffington Center on Aging, Baylor College of Medicine in Houston, Texas, is an expert on the biosynthetic aspects of DHEA.

    We have to do some long-term human experiments. The longest published one is 6 months. That’s not long enough for us to know what would happen if we took it for 10 or 20 years. Our knowledge about DHEA is basically what it was a couple of decades ago with estrogen. Even after twenty or so years of research on estrogen, we still don’t know its full effects.



    Moreover, we really can’t extrapolate from rodents to humans because they have very little circulating DHEA(S) levels. Although they do make it, they do so locally in the brain and in gonadal tissues. When DHEA is given to rodents, any dose is basically a pharmacological dose, not a physiological dose.


    Maria Majewska, Ph.D., Medications Development Division, National Institute on Drug Abuse, Rockville, Maryland.

    While we are waiting for more data, (Dr. Baulieu’s group is doing clinical studies at this time in France), the existing evidence already suggests that DHEA(S) replacement may be a safe and effective means of improving health and the quality of life during aging. However, we have yet to learn the right dosages.

    John Nestler, M.D., Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond. (As reported in the Annals NY Acad Sci 774: ix-xi, 1995.)

    The clinical issues that will have to be addressed include optimal DHEA dosage, form and amount, route of administration, and delineation of side effect profile. It is important that such studies be conducted before DHEA is casually administered to men and women, as some physicians in private practice are currently doing, because DHEA administration may be associated with some untoward effects. For example, DHEA can be converted to potent androgens, such as testosterone, which would masculinize women. Similarly, whether DHEA administration is associated with any change in prostatic volume or risk for prostatic cancer in men is currently unknown.



    Although the results of human DHEA studies appear promising and tantalizing, they still need to be confirmed in large-scale and properly controlled studies. Nonetheless, given the current groundswell in human DHEA-related research, I remain confident that these issues will be fully addressed within the next 5 to 10 years and predict that a therapeutic role for DHEA will be established. This could take the form of hormone replacement therapy (for example, starting DHEA administration around age 30 and keeping the serum level at its zenith) or pharmacologic therapy for specific disease indications.


    Joseph Mortola, M.D., Department of Reproductive Endocrinology, Beth Israel Hospital and Harvard Medical School, Boston, MA.

    I definitely think this hormone should be considered for replacement therapy, at least in the future, and perhaps now. DHEA has different effects on men and women, therefore, the recommendations and cautions would be different for each sex.



    DHEA administration can have an estrogenic effect in tissues of women. I’m only speculating, but if women are on estrogen replacement therapy and they want to add DHEA, they can probably decrease the estrogen dose by half. Even though metabolites of DHEA will stimulate breast tissue, they will do so less than estrogen itself, thus possibly decreasing the risk of breast tumor initiation that has been suggested by some studies on estrogen replacement.



    There has been speculation that testosterone, as well, may be appropriate for some women as replacement therapy. Since DHEA also gets converted into testosterone and other androgens in postmenopausal women, it may be a better way to deliver testosterone to tissues. However, lipid profiles and glucose levels should be monitored in women on DHEA.



    In men, DHEA should be considered as having more estrogenic effects rather than androgenic. DHEA has some effects by binding to androgen receptors located everywhere through our bodies. This would, in men, act as a buffer to the effects of testosterone. The data are clear that DHEA is beneficial in men, and certainly can’t hurt. But, the dosages have not been worked out.



    The replacement dose of DHEA in both sexes, in order to be effective, probably needs to be higher than 50 mg. Maybe up to 200 mg daily might be appropriate. However, we need some long-term studies.



    Based on everything I know, I would take DHEA if I were older. I’m 42 now. Perhaps in my fifties I would start supplementing, but, by then, I would have the luxury of knowing the results of another decade of studies. As to older people not wanting to wait that long, I can see a justification for them using it now, as long as they are monitored by a qualified physician.


    Drs. Yen, Morales and Khorram, Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA (As reported in Ann NY Acad Sci 774:128-142, 1995).

    DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant side effects. Further studies are needed.


    And now, the author’s opinion

    As indicated in this chapter, the consequences of supplementation with DHEA for anti-aging purposes is, at this time, not fully known in humans. There may be many positives, then again, there may be some totally unexpected long-term negative effects. No amount of studies on rodents will give us any definite clues to what will happen in us humans since, among many other differences in metabolism, rodents have little DHEA(S) circulating in their blood.



    Therefore, I recommend you be skeptical of anyone who tries to convince you to take megadoses of this hormone because his pet mouse has been on it, does nonstop jumping jacks all day long, and has outlived (and outbred) all the other mice in the neighborhood.



    Even given the beneficial effects that have been reporte, we don’t know whether the ideal dosage is 100 mg, 50 mg, or 10 mg. Is it better to supplement once daily, twice, or every other day? Does the timing of the dosage make a difference, ie, morning or evening? Will men respond more favorably than women; or vice versa? Is bringing DHEA levels back to those of “youth” really the best strategy, or is it better to raise your DHEA levels into the upper half of the normal range for your age? What form (sublingual, cream, micronized, etc.,) should be used?



    Having presented these uncertainties, I do not rule out that there could possibly be an anti-aging role for DHEA supplementation in middle-aged and older individuals. Many early studies show promise. Hormonal replacement therapy will continue being one of the most researched, and controversial, topics in health and medicine over the next few years, and even decades.



    Without a doubt, patients will be continuously asking their doctors whether they should supplement not only with DHEA, but with melatonin, growth hormone, progesterone, testosterone, estrogen, thyroid hormones, etc. etc. The uncertainties and controversies will continue for a very long time.



    If you are planning to supplement with DHEA, the very least I can recommend is that you make every effort to be supervised by a physician who is familiar with the research and has some amount of clinical experience with this steroid hormone.

  • Ray Sahelian MD Written by Ray Sahelian MD

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