Adrenal Diseases - Cushing's Syndrome
The Facts You Need To Know
On This Page:
Cushing's Syndrome Fact Sheet (pdf)
What is Cushing's Syndrome?
Cushing's Disease
Iatrogenic Cushing's Syndrome
Ectopic ACTH Production
Adrenal Cortex Tumors
What are the symptoms of Cushing's Syndrome?
How is Cushing's Syndrome diagnosed?
Why should a Cushing's patient consult an Endocrinologist?
How normal is an Cushing patient's life?
What is Cushing's Syndrome ?
Cushing's Syndrome is a disease caused by an excess of cortisol
production or by excessive use of cortisol or other similar steroid (glucocorticoid)
hormones.
Cortisol is a normal hormone produced in the outer portion, or cortex, of
the adrenal glands, located above each kidney. The normal function of
cortisol is to help the body respond to stress and change. It mobilizes
nutrients, modifies the body's response to inflammation, stimulates the
liver to raise the blood sugar, and it helps control the amount of water in
the body.
Another adrenal cortex hormone, aldosterone, regulates salt and
water levels which affects blood volume and blood pressure. Small amounts of
androgens (male hormones) are also normally produced in the adrenal cortex.
Cortisol production is regulated by adrenocorticotrophic hormone (ACTH),
made in the pituitary gland, which is located just below the brain.
When too much cortisol is produced in the adrenal glands, or an excess is
taken in treating other diseases, significant changes occur in all of the
tissues and organs of the body. All of these effects together are called
Cushing's Syndrome.
Spontaneous overproduction of cortisol in the adrenals is divided into
two groups - those due to an excess of ACTH and those that are independent
of ACTH.
Although almost all types of spontaneous Cushing's Syndrome are
ultimately caused by one type of tumor or another, little is known about
what makes these tumors occur. There does not appear to be any specific
genetic, immune, or environmental factor.
|
![](cushings.gif) |
Cushing's Disease
Cushing's Disease is the name given
to a type of Cushing's Syndrome caused by too much ACTH production in the
pituitary. Dr. Harvey Cushing first described a woman with signs and
symptoms of this disease in 1912, and in 1932 he was able to link the
adrenal overproduction of cortisol to an abnormality in the pituitary.
A pituitary tumor producing too much ACTH, stimulating the adrenals to
grow (hyperplasia) and to produce to much cortisol, is the most common type,
and this is called Cushing's disease. It is the cause of 70% of spontaneous
Cushing's syndrome.
Spontaneous Cushing's Syndrome and Cushing's disease can occur in
children and adults. Pituitary Cushing's disease generally occurs after
puberty with equal frequency in boys and girls. In adults, it has a greater
frequency in women than men, with most found at age 25 to 45. The total
incidence is about 5 to 25 cases per million people per year.
Cushing's disease is best treated with the surgical removal of the
pituitary tumor, usually with a technique called transsphenoidal resection
(behind the nose) by a neurosurgeon. Occasionally, the entire pituitary
gland will need to be removed or injured in order to cure the Cushing's
disease, leaving the person with a deficiency of ACTH and the other
pituitary hormones. This can be treated by giving replacement hormones for
cortisol, thyroid and gonadal (sex) hormones. Fertility can be restored with
special hormonal therapies. If the pituitary tumor cannot be removed,
radiation therapy to the pituitary can be used, but the improvement in the
Cushing's Syndrome is much slower.
Before transsphenoidal surgery became
available, the surgical removal of both adrenal glands was common, but this
always produced adrenal insufficiency and sometimes caused large ACTH
producing pituitary tumors to grow (called Nelson's syndrome). That is why
pituitary surgery rather than adrenal surgery is usually preferred for
Cushing's disease.
Iatrogenic Cushing's Syndrome
When cortisol or other glucocorticoid hormones (such as hydrocortisone,
prednisone, methyl-prednisolone or dexamethasone) are taken in excess of the
normal daily requirement for a prolonged period of time, it causes Cushing's
syndrome. This "iatrogenic" (caused by the treatment) form is unfortunately
a necessary side effect when high doses of these steroid hormones must be
used to treat certain life-threatening illnesses, such as asthma, rheumatoid
arthritis, systemic lupus, inflammatory bowel disease, some allergies, and
others.
Iatrogenic Cushing's Syndrome from taking steroid medication is extremely
common because of the widespread use of these medicines in treating many
illnesses.
If the Cushing's Syndrome is a side effect of taking high doses of
steroid hormones (iatrogenic), withdrawing these medicines will allow the
body to go back to normal. The ability to taper or stop the steroids,
however, depends on the type of disease being treated and the pattern of
response. Sometimes, steroids cannot be totally stopped or may be reduced
only to a limited degree because the illness being treated would worsen. In
that case, some degree of persistent Cushing's Syndrome would remain as an
unwanted side effect.
Treatment of the effects of steroid excess would
include management of high blood sugar with diet and medications,
replacement of potassium, treatment of high blood pressure, early treatment
of any infections, adequate calcium intake and appropriate adjustments in
steroid doses at times of acute illness, surgery or injury.
Ectopic ACTH Production
ACTH can also be produced outside the pituitary in a benign or malignant
tumor in the lung, thymus gland, pancreas, or other organ. This is called "ectopic"
ACTH production.
Ectopic ACTH as a cause of Cushing's Syndrome is more common because of
the high rate of lung cancer (about 660 per million per year), but it often
goes unrecognized. The incidence increases with age.
Ectopic ACTH producing tumors are usually malignant (cancer). Removing
this cancer or treating it with radiation or chemotherapy may help in
improving the Cushing's Syndrome. If the tumor is benign, or it can be
completely removed, surgery may be a cure. Most of the time, reduction of
the cortisol production from the adrenals with medications such as
metyrapone, amino-glutethimide or ketoconazole is useful while the
ACTH-producing tumor is treated.
Adrenal Cortex Tumors
When the source of excess cortisol production is a tumor of the adrenal
gland itself, then it is not dependent on ACTH. The tumor makes cortisol on
its own, and the other adrenal gland shrinks because ACTH production is
suppressed. Adrenal cortex tumors can be benign (an adenoma), or malignant
(a carcinoma) and are usually found on only one side. A very rare type is
caused by multiple benign adenomas on both sides.
Adrenal tumors are relatively rare, and cause Cushing's Syndrome in only
2 people per million per year for both adenomas and carcinomas. Both are
also 4 to 5 times more common in women than men.
Adrenal adenomas are always treated by surgically removing the tumor with
either an abdominal or side (flank) incision. The other adrenal is left in,
and will grow back to normal size or function. After the surgery,
replacement steroid hormones are given and slowly tapered over a few months
as the remaining adrenal responds to the normal ACTH production from the
pituitary.
Adrenal carcinomas (cancer) can be cured if removed early. Unfortunately,
they are usually discovered after they have already spread beyond the
adrenal gland and are then not curable. Chemotherapy including o, p'DDD and
other medicines are often used to try to control the tumor but do not cure
it. The excess cortisol production can be controlled with o, p'DDD or by
other medications like those mentioned for ectopic ACTH production:
metyrapone, aminoglutethimide and ketoconazole. These medicines can be used
to treat any form of inoperable or incurable Cushing's Syndrome, including
Cushing's disease, but they can have serious side effects and require very
careful monitoring and balancing with steroid hormone replacement therapies.
Surgical cure of the primary cause of the Cushing's Syndrome is always the
best, if possible.
What are the symptoms of Cushing's Syndrome?
Cortisol excess produces significant and serious change in the appearance
and health of affected individuals. Depending on the cause and duration of
the Cushing's Syndrome, some people may have more dramatic changes, some
might look more masculinized, some may have more blood pressure or weight
changes.
General physical features include a tendency to gain weight, especially
on the abdomen, face (moon face), neck and upper back (buffalo hump);
thinning and weakness of the muscles of the upper arms and upper legs;
thinning of the skin, with easy bruising and pink or purple stretch marks (striae)
on the abdomen, thighs, breasts and shoulders; increased acne, facial hair
growth, and scalp hair loss in women; sometimes a ruddy complexion on the
face and neck; often a skin darkening (acanthosis) on the neck. Children
will show obesity and poor growth in height.
On physical examination, a physician will notice these changes and will
also usually find high blood pressure and evidence of muscle weakness in the
upper arms and legs, and sometimes some enlargement of the clitoris in
females.
Symptoms usually include fatigue, weakness, depression, mood swings,
increased thirst and urination, and lack of menstrual periods in women.
Common findings on routine laboratory tests in people with Cushing's
Syndrome include a higher white blood count, a high blood sugar (often into
the diabetic range), and a low serum potassium. These will often reinforce a
physician's suspicion about Cushing's Syndrome. Ectopic Cushing's Syndrome
tends to present with less impressive classic features, but more dramatic
hypertension and loss of potassium, sometimes in the setting of weight loss
from the underlying cancer.
If untreated, Cushing's Syndrome will cause continued weakness of the
muscles, fatigue, poor skin healing, weakening of the bones of the spine
(osteoporosis), and increased susceptibility to some infections including
pneumonia and TB.
How is Cushing's Syndrome diagnosed?
Most people who appear to have some of the classic physical features of
Cushing's Syndrome (cushingoid appearance) do not actually have the disease.
After iatrogenic Cushing's is excluded, other causes of this appearance cn
be polycystic ovary syndrome (androgen excess from the ovaries), ovarian
tumors, congenital adrenal hyperplasia, ordinary obesity, excessive alcohol
consumption, or just a family tendency to have a round face and abdomen with
high blood pressure and high blood sugar.
Because Cushing's Syndrome is a rare but serious disorder, it is very
important to carefully exclude (rule out) other disorders and then separate
the different types, leading eventually to a specific cause that can be
treated. This process of testing and excluding usually takes days to weeks
and requires a lot of patience and cooperation by the person being tested.
After the initial history, physical exam and routine blood tests, the
first step is to prove cortisol excess with specific blood and 24 hour urine
tests for cortisol. Inappropriate cortisol production will then be evaluated
by doing a dexamethasone suppression test. Dexamethasone (steroid) pills are
given by mouth, then blood and urine are collected for cortisol and other
adrenal hormones. A screening test might be done initially with an overnight
test, but if it is abnormal, usually a 4 day test divided into low and high
dose dexamethasone is needed.
To separate ACTH dependent from independent
types, a blood test for ACTH in the morning is done. Blood and urine tests
for adrenal androgens are useful. Testing with other drugs, such as metyrapone and
CRH (corticotropin releasing hormone) may also be needed.
Once all of the blood and urine results are analyzed, they will establish
whether some type of Cushing's Syndrome is present, and should indicate
whether the disease is ACTH dependent (pituitary or ectopic) or independent
(an adrenal tumor). Localizing techniques such as CT or MRI are then used to
find the tumor. Often a pituitary tumor is tiny and hard to find, so a
special test of the release of ACTH from both sides of the pituitary (petrosal
sinus sampling) might be needed. Small tumors producing ectopic ACTH are
also sometimes difficult to localize and require repeated scans and x-rays.
Why should a Cushing's patient consult an Endocrinologist?
Iatrogenic Cushing's Syndrome is generally managed by the physician
prescribing the steroid hormones for the primary illness, such as asthma,
arthritis, or inflammatory bowel disease. Sometimes physicians are able to
decrease steroid doses by using other drugs in the treatment of these
diseases.
All of the types of spontaneous Cushing's
Syndrome should be carefully evaluated by an endocrinologist (a specialist
in hormonal disease) who has the knowledge and experience in choosing the
correct diagnostic studies and evaluating the results.
Finding the correct diagnosis often requires
prolonged testing and even repetition of tests. Quick shortcuts can be
misleading. Referrals for surgery or radiation should be coordinated by the
endocrinologist, who will also be directly involved in managing the patient
afterwards.
How normal is a Cushing patient's life?
The symptoms, disabilities and life-style of a person with Cushing's
Syndrome depend on the degree of cortisol excess, the duration of the
disease, the basic health of the person, but especially the type and
curability of the Cushing's Syndrome. If it is cured, all of the features of
the disease can resolve, but this may take as long as 2 to 18 months. During
that time, most people get annoyed and frustrated by the slow improvements
in physical changes and the combination of Cushing's and adrenal
insufficiency signs and symptoms (dizziness, weakness, nausea, loss of
appetite) as replacement steroid hormones are tapered and adrenal hormone
production slowly improves toward normal. Frequent calls and visits to
physicians are necessary.
If the Cushing's Syndrome is not curable, or if iatrogenic Cushing's Syndrome
must remain, these individuals will have to cope with persistent fatigue,
muscle weakness, abdominal and facial weight gain, depression, mood swings,
and all the other signs and symptoms mentioned earlier. Regular visits to a
physician for examinations, blood tests, and treatments of infections and
complications will be necessary and are often viewed as a sever burden.
The answers above were provided by
Dr. Paul Margulies, MD, FACP, FACE,
NADF Medical Director
Clinical Associate Professor of Medicine, New York University Medical School
|