by Ward Dean,
and Steven Wm. Fowkes
From the October 15th,
1993 issue of Smart
Copyright (c) 1993, 1997. All rights reserved.
Used with permission from Author
(pronounced dee-hi-dro-epp-ee-ann-dro-stehr-own), or
DHEA as it is more often called, is a steroid hormone
produced in the adrenal gland. It is the most abundant
steroid in the bloodstream and is present at even higher
levels in brain tissue. DHEA levels are known to fall
precipitously with age, falling 90% from age 20 to age
90. DHEA is known to be a precursor to the numerous
steroid sex hormones (including estrogen and testosterone)
which serve well-known refunctions, but the specific
biological role of DHEA itself is not so well understood.
It is difficult for searchers to separate the effects
of DHEA from those of the primary sex steroids into
which it is metabolized. The apparent lack of any direct
hormone action for DHEA has prompted the suggestion
that it may serve the role of a “buffering hormone”
which would alter the state-dependency of other steroid
hormones. Although the specific mechanisms of action
for DHEA are only partially understood, supplemental
DHEA has been shown to have anti-aging, anti-obesity
and anti-cancer influences. In addition, it is known
to stabilize nerve-cell growth and is being tested in
Our understanding of the
specific mechanisms of DHEA in metabolism has recently
been advanced by the publication of The Biologic
Role of Dehydroepiandrosterone (DHEA), edited by
Mohammed Kalimi and William Regelson . This book
presents 24 chapters from scientists around the world
who are conducting DHEA research. The breadth of the
work is impressive. As Drs. Regelson, Kalimi and Loria
stated in their introductory remarks, “DHEA modulates
diabetes, obesity, carcinogenesis, tumor growth, neurite
outgrowth, virus and bacterial infection, stress, pregnancy,
hypertension, collagen and skin integrity, fatigue,
depression, memory and immune responses.” With this
wide range of potential clinical uses, it is amazing
that more books about DHEA have not been written.
The introductory chapter,
by the editors and Roger Loria, briefly reviews DHEA’s
biochemistry, endocrinology, and potential clinical
uses. They contend that it is perhaps the most significant
endocrine biomarker known, and further postulate that
all of its effects may be explained by its action as
a precursor hormone which provides “a host of steroid
progeny with which to maintain the broad balance of
host response related to species and individual survival.”
DHEA and Cancer
Early reports from England
[Bulbrook, 1962, 1971] suggested that DHEA was abnormally
low in women who developed breast cancer, even as much
as nine years prior to the onset or diagnosis of the
disease. Of the 5000 women followed in the study, 27
developed cancer. Most of the 27 had abnormally low
levels of DHEA. If low DHEA levels contributed to breast
cancer, might the opposite be true? Many years later,
Dr. Arthur Schwartz of Temple University found that
supplemental DHEA significantly protected cell cultures
from the toxicity of carcinogens. Cell cultures usually
respond to powerful carcinogens with mutations (changes
in DNA), transformations (changes in cell appearance),
and a high rate of cell death. But when Schwartz added
DHEA along with the carcinogen, all three of these effects
were significantly diminished.
Subsequent studies [Schwartz,
1979] identified powerful protective effects of supplemented
DHEA for breast-cancer-prone mice. The results of the
experiment was clear after 8 months. The control animals
were “getting cancer left and right” while the DHEA
animals had no tumors. In two later studies with different
strains of mice, Schwartz found 75% and 100% reductions
in tumor incidence at 8 months of age and 50% and 75%
reductions at 15 months of age [Schwartz, 1981; 1984].
DHEA has demonstrated protective effects for cancers
of the skin, lungs, bowel, breast and liver. According
to William Regelson, “Whenever [DHEA] has been tested
in a model of carcinogenesis and tumor induction, DHEA
has preventative effects.” Although DHEA is now beginning
to be tested in human cancer, it is still to early to
know whether the successes achieved in animals will
be realized in humans.
The Anti-Obesity Factor
At about the same time
that Schwartz was investigating the anti-cancer properties
of DHEA, Dr. Terrence T. Yen was studying the effect
of DHEA on genetically obese mice. Although the DHEA-treated
mice ate normally, they remained thin — and they lived
longer than control mice. This “leanness” effect was
also conspicuously noted by Dr. Schwartz. In another
experiment, Dr. M. P. Cleary found that even middle-aged
obese rats lost weight when fed DHEA-supplemented food.
Diabetes, a typical complication of obesity, was also
DHEA and Glucose Metabolism
Investigators have shown
that DHEA inhibits glucose-6-phosphate dehydrogenase
(G6PDH), an enzyme that breaks down glucose. There are
two glucose-metabolizing pathways in the body, the catabolic,
energy-yielding pathway and the anabolic, biosynthetic
pathway. G6PDH happens to be the first enzyme in the
biosynthetic pathway, the one which results in the synthesis
of fatty acids and ribose (the sugar used in making
deoxyribonucleic acid, or DNA). In simple language,
G6PDH turns glucose into fat.
DHEA’s inhibition of G6PDH
may redirect glucose from anabolic fat-production into
catabolic energy metabolism, thus creating a leaner
metabolism. This function of DHEA is well reviewed by
Arthur Schwartz and colleagues in their chapter on “The
Biological Significance of Dehydroepiandrosterone” in
The Biologic Role of Dehydroepiandrosterone.
They assert that DHEA-mediated reductions in ribose-5-phosphate
activity may be centrally responsible for the anti-tumor
promoting, anti-tumor initiating, and possibly the anti-atherogenic
properties of DHEA. They also note that DHEA 1) produces
hepatomegaly (liver enlargement), 2) stimulates liver
catalase activity (a protective antioxidant enzyme),
and 3) causes proliferation of peroxisomes (cellular
organelles which specialize in oxidative processing
and the decomposition of hydrogen peroxide). The absence
of such influences with synthetic analogs of DHEA (like
16-alpha-fluoro-5-androsten-17-one) prompts Schwartz
and colleagues to recommend that such analogs be considered
for clinical applications in humans. Toxicity factors
still need to be assessed.
DHEA and Appetite
In different experiments,
DHEA supplementation has resulted in increased, decreased
and unchanged food consumption. Dr. Schwartz found that
it is the level of dietary fat influences food consumption.
DHEA-treated rats on a high-fat diet ate less food than
control rats while those on a low-fat diet ate more.
Since DHEA inhibits G6PDH
activity and suppresses the body’s ability to synthesize
fat from carbohydrate, dietary sources of fat become
more important. This can affect changes in appetite.
But despite possible increases in food intake, DHEA-treated
animals consistently weighed less than control animals.
In other words, increases in appetite, when indulged,
did not negate the anti-obesity property of DHEA.
DHEA and Aging
The body’s production of
DHEA drops from about 30 mg at age 20 to less than 6
mg per day at age 80. According to Dr. William Regelson
of the Medical College of Virginia, DHEA is “one of
the best biochemical bio-markers for chronologic age.”
In some people, DHEA levels decline 95% during their
lifetime — the largest decline of an important biochemical
In animal studies, DHEA
extends rodent lifespans up to 50%. The animals not
only lived longer, they looked younger. The graying,
course-haired controls could easily be distinguished
from the sleek, black-haired, DHEA-treated animals.
DHEA levels are directly
related to mortality (the probability of dying) in humans.
In a 12-year study of over 240 men aged 50 to 79 years,
researchers found that DHEA levels were inversely correlated
with mortality, both from heart disease and from all
causes. This finding suggests that DHEA level measurements
can become a standard diagnostic predictor of disease,
mortality and lifespan. Furthermore, if animal results
hold true, supplemental DHEA may prevent disease, reduce
mortality, and extend lifespan in humans.
Enhancing Brain Function
DHEA may also be intimately
involved in protecting brain neurons from senility-associated
degenerative conditions, like Alzheimer’s disease. Not
only do neuronal degenerative conditions occur most
frequently when DHEA levels are lowest, but brain tissue
contains many times more DHEA than is found in the bloodstream.
One of the scientists at the forefront of this field
of research is Dr. Eugene Roberts who found that very
low concentrations of DHEA were found to “increase the
number of neurons, their ability to establish contacts,
and their differentiation” in cell cultures. He also
found that DHEA also enhanced long-term memory in mice
undergoing avoidance training. It may play a similar
role in human brain function.
Drs. Roberts and Fitten
report initial research on “Serum steroid levels in
two old men with Alzheimer’s disease before, during
and after oral administration of DHEA” in the book The
Biologic Role of Dehydroepiandrosterone. Roberts’
and Fitten’s data are the best we’ve seen regarding
acute and chronic changes in numerous hormone levels
following various oral doses of DHEA (see adjacent graphs).
Because of the short peak duration of DHEA (heavier
line in illustration), they recommend that future studies
or therapeutic trials use time-release capsules or transdermal
patches to provide more uniform delivery of DHEA.
Levels of pregnenolone
and 17-alpha-pregnenolone, the direct precursors to
DHEA, were too low to be measured in the two patients
illustrated, but Roberts and Fitten present data from
three other Alzheimer’s patients. Their data indicate
that in all three patients, “control values for pregnenolone
and 17-alpha-pregnenolone not only were below the means
for the population controls, they were lower than the
lowest values.” In other words, the highest of the Alzheimer’s
patients was lower than the lowest of the population
controls. When they were administered 400 mg of DHEA,
all three experienced decreased levels of 17-alpha-pregnenolone.
Pregnenolone levels increased in two patients and fell
in the third. In the two patients experiencing increased
pregnenolone and decreased 17-alpha-pregnenolone in
response to DHEA, levels of 17-alpha-pregnenolone rebounded
strongly at 24 hours. Roberts and Fitten suggest that
“a prolonged inhibition of 17-alpha hydroxylation occurred
as a result of continued DHEA intake.”
DHEA and Immune Function
DHEA is known to enhance
general immune response. Oral and subcutaneous DHEA
has been observed to protect rodents against the lethality
of RNA and DNA viruses, and lethal bacterial infections.
Drs. Loria, Regelson and Padgett report in The Biologic
Role of Dehydroepiandrosterone (DHEA) that a single
subcutaneous dose of DHEA is considerably more
effective in protecting against infection than oral
dosing. Intraperitoneal [within the abdominal cavity]
injections were completely ineffective.
Dr. Loria and colleagues
noted that subcutaneous dosing did not result in the
typical weight loss observed with oral DHEA. Presumably
it works by a different mechanism. DHEA has been reported
to counteract the thymic involution [shrinking of the
thymus gland] and immuno-suppression caused by corticosteroids.
But the special role of skin tissues in the immune facilitating
properties of DHEA suggest a different mechanism is
involved. Cutaneous immune cells, such as Langerhans
cells and keratinocytes, are believed to play a role
in “immune surveillance” and “antigen presentation.”
These cells may be a site of DHEA’s action. Subcutaneous
injection of DHEA results in the “formation of a local
deposit leading to a relatively prolonged exposure to
the lymphoid system.” DHEA skin patches might provide
a similar exposure.
The delay in protective
effect of subcutaneous DHEA has prompted Loria and colleagues
to postulate that a DHEA metabolite is involved in cutaneous
immune enhancement. In a recent paper [Loria and Padgett,
1993], they advance androstenediol [5-androsten-3-beta-17-beta-diol]
as the active metabolite, the production of which is
predominantly localized in the skin and brain. They
found that androstenediol was significantly more effective
than DHEA (10,000 times more with coxsackievirus B4!).
Neither DHEA nor androstenediol
have any direct (in vitro) antiviral activity.
The amount of viral load in heart, spleen, pancreas,
liver and blood tissues was unaffected by either DHEA
or androstenediol administration. The effect of these
steroids appears to be strictly mediated through stimulation
of lymphocytes, lymphoid organs, and immune-modulating
cytokines [immune hormones].
DHEA: The Buffering Steroid?
DHEA may be unique among
hormones for it’s lack of specificity forhormone receptor
sites. Just as vitamin E has never been shown to have
a specific metabolic role (it is only proven essential
as a general antioxidant), DHEA may serve an equally
general purpose. “DHEA is the first example of a buffer
action for hormones that I know of,” states William
Regelson. “It is a broad-acting hormone that only demonstrates
itself under a specific set of circumstances. In that
way, it is like a buffer against sudden changes in acidity
or alkalinity. That is why when you get older, you’re
much more vulnerable to the effects of stress. As DHEA
declines with age, you are losing the buffer against
the stress-related hormones. It is the buffer action
that [helps prevent] us from aging.” The decrease of
DHEA with age may result in gradual decline of a system
for suppressing enzyme systems responsible for creating
the building blocks of new cells, like lipids, nucleic
acids (RNA and DNA) and sex steroids. The resulting
rise in enzymatic activity in advanced age may be responsible
for the proliferative events (cancer) and degenerative
disease that become more frequent in advanced age. In
this respect, DHEA might be best considered to be an
anti-hormone, which might “de-excite” steroid-sensitive
receptors that would otherwise lead to enhanced metabolic
Exact dosages for humans
have not been clearly determined. Daily dosages vary
from 5 to 10 mg to as much as 2000 mg, with 5, 10, 25
and 250 mg being the range for typical tablet and capsule
sizes. DHEA is usually split into 2-4 daily doses, especially
at the higher dosage levels.
We recommend that dosage
be adjusted to bring blood DHEA and DHEA-S measurements
towards young-adult levels. These blood tests can be
ordered by your physician (don’t forget to get your
first test before you start taking DHEA).
Because of its generally
universal function in human metabolism, DHEA is being
associated with numerous human maladies. For example,
DHEA has recently been found to have a highly statistically
significant correlation with vertebral bone density
in postmenopausal women suggesting that DHEA (and other
weak androgens) may protect against osteoporosis. This,
and its low toxicity, may tend to give DHEA the same
panacea stigma that the antioxidants vitamin E and C
In Europe, DHEA is already
available as a drug in 5 and 10 mg doses (although it
has been hard to obtain). It is used primarily for the
treatment of menopause. In the United States, DHEA must
first be approved as a drug by the FDA before it can
be marketed for medical purposes. Unfortunately, this
is an adversarial process (the drug companies advocating
for the drug and the FDA demanding proof of efficacy
and safety) which takes up to 100 million dollars and
a decade to accomplish. Without a patent to restrict
competition, prices cannot be raised high enough to
recover the investment in the approval process. DHEA
is an unpatentable substance.
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sulfate, mortality, and cardiovascular disease. New
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JL and Spicer CC. Abnormal excretion of urinary steroids
by women with early breast cancer. Lancet 2:
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JL and Spicer CC. Relation between urinary androgen
and corticoid excretion and subsequent breast cancer.
Lancet 2: 395-98, 1971.
Chen TT, et al.
Prevention of obesity in Avy/a mice by dehydroepiandrosterone.
Lipids 12: 409-13, 1977.
Cleary MP and Fisk
JF. Anti-obesity effect of two different levels of dehydroepiandrosterone
in lean and obese middle-aged female Zucker rats. International
Journal of Obesity 10(3): 193-204, 1986.
Coleman DL, Leiter
EH and Applezweig N. Therapeutic effects of dehydroepiandrosterone
metabolites in diabetes mutant mice (C57BL/KsJ-db/db).
Endocrinology 115: 239-43, 1984.
Coleman DL, Leiter
EH and Schweizer RW. Therapeutic effects of dehydroepiandrosterone
(DHEA) in diabetic mice. Diabetes 31: 830-33,
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RW and Leiter EH. Effect of genetic background on the
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in diabetes-obesity mutants and in aged normal mice.
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de Peretti E and
Forest MG. Pattern of plasma dehydroepiandrosterone
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Kahn, Carol. Beyond
the Double Helix: DNA and the Quest for Longevity,
Times Books, 1985, page 143. A thorough and highly readable
“inside” account of DHEA research.
Loria RM, Regelson
W and Padgett DA. Immune response facilitation and resistance
to virus and bacterial infections with dehydroepiandrosterone
(DHEA). In: The Biologic Role of Dehydroepiandrosterone
(DHEA), Mohammed Kalimi and William Regelson [Eds],
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DA. Androstenediol regulates systemic resistance against
lethal Infections in mice. Annals of NY Academy of
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colon tumorigenesis in Balb/c mice by dehydroepiandrosterone.
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JL, Rizer RL and Vogelman JH. Age changes and sex differences
in serum dehydroepiandrosterone sulfate concentrations
throughout adulthood. J Clin Endocrinol Metab
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AG. Effect of food restriction, dehydroepiandrosterone,
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to mouse skin DNA. J Gerontology 38: 8-12, 1983.
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mice by long-term treatment with dehydroepiandrosterone.
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Pearson DV, Acton JM and Greenberg MM. Prevention of
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