4
Stem Cells(continued from p. 3)
Cholesterol is first converted to pregnenolone by
cytochrome P450scc, which is present in every adrenal cortical
zone. Pregnenolone is converted to progesterone by
3ß-hydroxysteroid dehydrogenase, which is also present in
all adrenal cortical zones. Progesterone is converted to
deoxycorticosterone by cytochrome P450c21, which is
present in both the glomerulosa and the fasciculata.
Aldosterone, a mineralocortiocoid released by angiotensin
II stimulation, is synthesized from deoxycorticosterone by
cytochrome P450aldo, which is present only in the
glomerulosa. On the other hand, cortisol, a glucocorticoid
released by the adrenocortictropic hormone (ACTH) stimulation,
is synthesized from deoxycortisol by the enzyme
11ß-hydroxylase, which is found only in the fasciculata.
When these biochemical pathways are disturbed, the
production of the steroid hormones is altered, often leading
to states of adrenal insufficiency. In congenital adrenal
hyperplasia, most patients have mutations of the 21-
hydroxylase gene that encodes P450c21, a key enzyme in
the production of both aldosterone and cortisol. Current
medical therapy for adrenal insufficiency employs the
administration of steroid hormones to replace the missing
hormones. Such treatment is life-saving but is not ideal
because the body’s need for steroid hormones varies with
the physiologic states. During periods of stress, the need for
steroid is increased considerably, and the normal feedback
regulation in the body would increase the production of
steroids automatically. The current medical therapy for
adrenal insufficiency does not have such automatic adjustment.
Instead, extra steroids are empirically given during
stress states such as a significant illness.
Traditionally the adrenal cortex is viewed as a static organ
where the cells do not grow in response to physiological
changes. More recently, it has been shown that this view is
incorrect. The functional zones within the adrenal cortex
are dynamic layers of cells that do respond to changes in
physiologic need by cell growth. For example, when excess
ACTH is present, the fasciculata increases in size to produce
additional glucocorticoids. Alternatively, when a salt-deficient
diet is given, the glomerulosa increases in size to produce
extra mineralocorticoids to retain salt within the body.
It is speculated that the additional cells that expand the
functional zones are generated from stem cells that reside in
an area between the glomerulosa and fasciculata. Adrenal
cortical cells in this area are actively growing on a continuous
basis. This can be demonstrated by using a special tracer,
bromodeoxyuridine, to label the adrenal cortical cells
that are making new DNA. With special staining, such
labeled cells appear as dark brown spots between the
glomerulosa and the fasciculata soon after the label is given,
and the labeled cells migrate toward the adrenal capsule and
medulla over a period of several days (Figure 2).
There are numerous other studies in the literature that
strongly suggest the existence of stem cells within the adrenal
cortex. These stem cells are capable of making new specialized
adrenal cortical cells that produce different steroid
hormones. If such adrenal cortical stem cells could be used
to regenerate functional cortical tissues in patients with
adrenal insufficiency, then the physiological secretion of
steroid hormones could be restored.
In our laboratory, we have developed methods to isolate
and to grow adrenal cortical cells from mice. Furthermore,
we have transplanted these cells into other normal mice. We
found that these adrenal cortical cells continued to express
many characteristics of the normal adrenal cortex after
transplantation. These observations suggest that it would be
feasible to develop similar techniques for humans whereby
adrenal cortical stem cells can be transplanted into patients
with adrenal insufficiency. As a first step toward that goal,
we are working to identify the adrenal cortical stem cells
that can regenerate the adrenal cortex. If successful, the next
phase of the experiments will utilize such stem cells for gene
transfer so that a normal copy of the gene such as 21-
hydroxylase can be inserted into these stem cells.
Ultimately, the objective is to procure adrenal cortical stem
cells from patients with congenital adrenal hyperplasia so
that these cells may be genetically modified in the laboratory.
The corrected adrenal cortical stem cells that carry a normal
copy of the gene will be transplanted back into patients
with congenital adrenal hyperplasia. For those patients who
do not have adrenal glands, it may still be possible to transplant
adrenal cortical stem cells from another donor, but
this will likely require immunosuppressive drugs to prevent
rejection. With the proper technique, the transplanted adrenal
cortical stem cells will able to regenerate functional
adrenal cortical tissues as a potential cure for adrenal insufficiency.
Figure 2. A cross section through the adrenal
cortex. Newly produced cells in the adrenal cortex
are labeled as dark brown spots. Most of
these cells are located between the glomerulosa
(G) and the fasciculata (F). These cells also
spread out towards the outer edge of the adrenal
cortex and the reticularis ®.
Brittle Bones Can Affect
Older Men As Well
Fractures less common but more lethal for men
than for women, experts say.
By E.J. Mundell
HealthDay Reporter(Reprinted using the Freedom of Information Act.)
SUNDAY, July 10 (HealthDay News) — Everyone
knows that women need to fend off osteoporosis as they
age. But what is less well-known is that 30 percent of elderly
men who suffer a hip fracture will die within a year of
that fracture — double the rate for older female patients.
But despite this increased risk, experts say many men
view brittle bones as a “woman's problem.”
Too many doctors may also share that view: One recent
U.S. study, published in the June issue of the journal
Osteoporosis International, “validated what we thought —
that men who have fractures are woefully undertreated. Just
one in every six men who had a spine or hip fracture was
treated with osteoporosis medications” to strengthen ailing
bones, said Dr. Thomas J. Weber, an assistant professor of
medicine at Duke University Medical Center.
According to the same study, just 1.1 percent of men
brought to the hospital for a serious fracture received a bone
density test to evaluate their overall risk.
“Now, doctors wouldn't hesitate to do that for a woman,
but it seems we just don't think of it in terms of men,”
Weber said.
It's true that men start out with denser, healthier bones
than women.
“Women have less bone to begin with, and then they get
a big hit at menopause,” said Dr. Joseph Lane, chief of the
metabolic bone disease service at the Weill Cornell Medical
College's Hospital for Special Surgery in New York City.
“The overall rate of bone loss for men and women is the
same, but because men start higher they don't get into trouble
as quickly — osteoporosis isn't an issue for men until 70
and beyond,” he said.
But when a fracture occurs in the elderly, brittle bones
can quickly become a life-or-death concern.
“There are a number of reasons people can die after fracture,”
Weber said. “They may have underlying cardiovascular
disease that leads to congestive heart failure. They may
develop infection and there's a suggestion, based on some
evidence, that perhaps in 25 percent of male patients death
is related to the consequences of the hip fracture itself.”
While menopause is a major cause of bone deterioration
in women, factors such as smoking, alcohol consumption
and the use of certain medicines increase fracture risks for
men, Lane said. The gradual age-related decline in circulating
testosterone is another factor. “A young guy has a testosterone
value of about 1,000 and older men are down to
about 300,” he said.
All of these risk factors are preventable, either through
quitting smoking and heavy drinking, or via pharmaceutical
means, said Lane, who is also a spokesman for the
American Academy of Orthopaedic Surgeons.
Then there's diet and exercise.
“In general, men over the age of 50 should be getting
1,200 mg of calcium a day from diet, or diet and supplements
combined,” Weber said. Lane advises men to use calcium
citrate — not bicarbonate — supplements, because
the bicarbonate formulation raises risks for kidney stones.
The current recommended daily allowance for another
bone-strengthener, vitamin D, is 400 International Units
(IU) per day for older men, but Weber said that level is currently
under review and will no doubt be revised.
“I think maybe upwards of 800 to 1,000 IU can be safely
recommended for men,” he said. Many foods, including
milk, come fortified with vitamin D (check the label) and
cod liver oil capsules are particularly high in the nutrient.
Skin also manufactures vitamin D under strong sunlight.
“It has to do with the sun's angle, though, so go out there
between 10 a.m. and 2 p.m. rather than taking a walk in the
early morning,” Weber said.
As for exercise, its benefits are more about balance than
bones, according to Weber. “Exercise's effects on the skeleton
tend to be fairly modest,” he explained. “When we prescribe
exercise for older people we're doing it not only to
help bone density but to increase strength and reduce their
risk of falls.”
Lane agreed. “You need two things for a fracture: bad
bones and a fall. There's an easy way to tell if you're at high
risk for falling: try standing on one leg for 12 seconds. If
you can't do that, then by definition you're an unsteady
individual who needs fall protection” such as sturdy shoes,
a cane or walker, he said.
But failing balance can be restored, and one of the
world's oldest interventions remains among the most effective.
“The most successful method is Tai Chi,” Lane said. “All
of the YMCAs in New York now teach Tai Chi, and we send
all the people who fail the one-leg test to the Y to learn it.”
More information
Bone up on bone loss at the American Academy of
Orthopaedic Surgeons.
(SOURCES: Thomas J. Weber, M.D., assistant professor,
medicine, division of endocrinology, metabolism and
nutrition, Duke University Medical Center, Durham, N.C.;
Joseph Lane, M.D., chief, metabolic bone disease service,
Hospital for Special Surgery, Weill Medical College of
Cornell University, New York City, and spokesman,
American Academy of Orthopaedic Surgeons)
Copyright © 2005 ScoutNews, LLC. All rights reserved.
HealthDayNews articles are derived from various sources
and do not reflect federal policy. healthfinder® does not
endorse opinions, products, or services that may appear in
news stories. For more information on health topics in the
news, visit the healthfinder® health library.
We subscribe to the HONcode principles of the HON
Foundation.
5
As previously reported, we have graciously been named
as a patient advocacy group to a research project titled Rare
Diseases Clinical Research Network, funded by the
National Institutes of Health Office of Rare Diseases. The
portion of the project that we are involved with is called the
Rare Genetic Steroid Disorders Consortium (RGSDC.) It is
being directed by Dr. Maria I. New, an highly esteemed
pediatric endocrinologist at Mount Sinai School of
Medicine and medical advisor to National Adrenal Diseases
Foundation. The adrenal disease that is being studied
directly is Congenital Adrenal Hyperplasia, a condition
wherein the steroid hormones cortisol and aldosterone cannot
be synthesized, and over production of adrenal androgens
is the result. The website for this project can be visited at:
http://rarediseasesnetwork.epi.usf.edu/rgsdc/index.htmQ. If I were to have a blood test for
Adrenal Autoantibodies, exactly
which autoantibodies would be
tested? I have Premature Ovarian Failure, diagnosed in
1984, and Primary Adrenal Insufficiency diagnosed in
1994. My endocrinologist told me at diagnosis that POF is
a 'red flag' for future development of Addison's disease. Is
the same autoantibody vs. steroid enzymes at work in both
diseases?
A. The best antibody test for Addison's disease is the
anti-21 hydroxylase test, available by commercial labs.
Avoid the older “anti-adrenal antibody” test. I am not
aware of any anti-ovary antibody test currently available.
Q. I live in Argentina. I am taking hydrocortisone (50
mg per day) and fludocortisone: one pill per day.
My problem is that I suffered from high blood
pressure before I was diagnosed with Addison’s, so I can not
take extra salt, and because of the warm weather, I sweat a lot
and am losing too much salt and my endo does not know
how to control it.
A. People who have Addison's disease as well as hypertension
still need to take mineralocorticoid replacements
like fludrocortisone, but often have to modify
the regimen. There is a significant amount of mineralocorticoid
activity in the hydrocortisone, and 50 mg is a fairly large
dosage. If there are any signs of cortisone excess, such as
weight gain, facial roundness, stretch marks or facial redness,
it may be useful to work with your doctor on a slight reduction
in the hydrocortisone dose first. Next, a reduction in the
dose of fludrocortisone may help lower the blood pressure. I
have used doses as low as 1/2 pill every 3 days. Finally, antihypertensive
medication can be added, but never a diuretic.
6
Medications like calcium channel blockers, beta blockers, and
alpha blockers can be used safely in Addison's disease.
Q. I have severe adrenal deficiency. I have been placed
in the hospital several times because of my condition.
When they administer the IV of isotonic
saline, how much should they give me? I have been given a
different amount each time I have been in the hospital. Any
information you can give me would be most helpful.
A. The amount of iv saline given for an adrenal crisis
varies with the degree of dehydration, the severity of
the signs of adrenal insufficiency, and whether there are
other medical conditions, such as heart disease that might
limit the ability of the body to utilize the fluid. Most of the
time, if there are no other disorders, one liter of saline should
be given along with 100 mg of hydrocortisone within the first
hour, then 100 to 200 ml per hour after that until blood pressure
and electrolytes (sodium and potassium) are back to normal.
Q. I have read that diagnosing adrenal fatigue can be
very tricky and there are many types of different
tests. Could you please share with me as to which
one you think is the most accurate?
A. “Adrenal fatigue” is not a recognized medical diagnosis.
Addison's disease is the correct term for primary adrenal
insufficiency and is diagnosed with an abnormal
lack of response to ACTH or Cortrosyn, elevated levels of
ACTH, positive 21-OH antibodies (if autoimmune) and characteristic
symptoms and physical findings. Clearly, people with
Addison's disease must go through a period of relative loss of
adrenal reserve before they present with the full set of abnormalities
of total adrenal failure. During that phase there may be
partial adrenal insufficiency that may give test results that are in
between normal and classic Addison's. I would use the term
early or partial adrenal insufficiency not “adrenal fatigue”. I
think that term is used by people who propose that the adrenals
“wear out” from various stresses and miss the point that
Addison's disease is not caused by stress, but by specific injury
from antibodies, hemorrhage, infections, tumors, or surgery.
Q & A
By Paul Margulies, M.D., FACE, FACP
WEBSITES OF INTEREST
The Canadian Addison Society (CAS) is updating their
website. Please feel free to visit at:
http://www.addisonsociety.ca/beta/index.htmlFor CAS’ emergency cortisol injection instructions, go to:
http://www.addisonsociety.ca/beta/injection.html(Please keep in mind that the instructions there refer to
Pfizer’s Solu-Medrol and Solu-Cortef, supplied in their
handy “acto-vials”. Accurate instructions for your medication
would depend on what type of emergency injection
you have been prescribed.)
http://www.BenefitsCheckUp.org/rxThis website was created to help older adults with information
on the Medicare low-income subsidy, the extra help
that covers 95 percent of drug costs on average for people
with Medicare who have limited means, through the
Medicare Modernization Act of 2003.