DHEA
by
Ward
Dean,
M.D.,
and
Steven
Wm.
Fowkes
From
the
October
15th,
1993
issue
of
Smart
Drug
News.
Copyright
(c)
1993,
1997.
All rights reserved.
Used
with
permission
from
Author
Dehydroepiandrosterone
(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
Alzheimer’s
patients.
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
[1990].
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
dramatically
decreased.
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
yet
documented.
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
activity.
Dosage
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).
Conclusion
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
suffer.
Regulatory
Difficulties
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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