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Cushing Disease
Cushing Disease
C2
Physiology Laboratory
Small Group Discussion
Output
Cushing's disease is rare, affecting 10 to 15 people per million each year, most
commonly adults between 20 and 50 years of age. Women account for more than 70
percent of cases.
Cushing's syndrome is much more common than Cushing's disease. The most
common cause of elevated cortisol levels is taking medications that have cortisol,
including: hydrocortisone, prednisone pills, skin ointments, asthma inhalers and joint
steroid injections
An adrenal tumor
"Pseudo-Cushing's," chronically elevated levels of cortisol due to: depression,
alcohol abuse, anorexia nervosa or high estrogen levels
Patients with "pseudo-Cushing's" may be difficult to distinguish from those with true
Cushing's. Your doctor may need to order specialized hormonal tests to clarify the
diagnosis.
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Symptoms
Although uncommon, some patients with Cushing's disease have large pituitary
tumors (macroadenomas). In addition to the severe hormonal effects related to increase
blood cortisol levels, the large tumor can compress adjacent structures leading to:
Vision loss
o When large pituitary adenomas (macroadenomas) grow upward into the
brain cavity, the tumor can elevate and compress the optic chiasm, the
part of the brain where the optic nerves partially cross.
o A loss of the outer peripheral vision occurs, called a bitemporal
hemianopsia
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When severe, a patient can only see what is directly in front of them. Many
patients do not become aware of their visual loss until it is quite severe.
Other visual problems can include:
o Loss of visual acuity (blurry vision), especially if the macroadenoma grows
forward and compresses an optic nerve.
o Inability to perceive colors as brightly as usual
Increased compression of the normal gland can cause hormone insufficiency,
called hypopituitarism. The symptoms depend upon which hormone is involved.
o Reduction of sex hormones, luteinizing hormone (LH) and follicle-
stimulating hormone (FSH).
In men, this can lead to a low testosterone level, causing
decreased sexual drive and impotence.
In some cases, there can be loss of body and facial hair.
In women, this can lead to infertility.
o Large pituitary tumors can slightly elevate blood prolactin levels. Doctors
think this occurs because of compression of the pituitary stalk, the
connection between the brain and the pituitary gland. It is called the "stalk
effect."
In premenopausal women, this can lead to reduction or loss of
menstrual periods and/or breast milk production (galactorrhea).
Prolactin levels are only slightly elevated, as opposed to
prolactinomas in which the prolactin level is usually very high.
Causes
Excess levels of the hormone cortisol are responsible for Cushing syndrome.
Cortisol, which is produced in the adrenal glands, plays a variety of roles in your body.
For example, cortisol helps regulate your blood pressure and keeps your cardiovascular
system functioning normally.
Cortisol also helps your body respond to stress and regulates the way you
convert (metabolize) proteins, carbohydrates and fats in your diet into usable energy.
However, when the level of cortisol is too high in your body, you may develop Cushing
syndrome.
Cushing syndrome can develop from a cause outside of your body (exogenous
Cushing syndrome). One example is taking oral corticosteroid medications in high
doses over an extended period of time. These medications, such as prednisone, have
the same effect in the body as does cortisol produced by your body.
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Oral corticosteroids may be necessary to treat inflammatory diseases, such as
rheumatoid arthritis, lupus and asthma, or to prevent your body from rejecting a
transplanted organ. Because the doses required to treat these conditions are often
higher than the amount of cortisol your body normally needs each day, side effects from
excess cortisol can occur.
The condition may also be due to your body's own overproduction of cortisol
(endogenous Cushing syndrome). This may occur from excess production by one or
both adrenal glands, or overproduction of the adrenocorticotropic hormone (ACTH),
which normally regulates cortisol production, In these cases, Cushing syndrome may be
related to:
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ACTH and is associated with disorders of the adrenal glands. The most common of
these disorders is a noncancerous tumor of the adrenal cortex, called an adrenal
adenoma.
Cancerous tumors of the adrenal cortex (adrenocortical carcinomas) are rare, but
they can cause Cushing syndrome as well. Occasionally, benign, nodular
enlargement of both adrenal glands can result in Cushing syndrome.
When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid
hormones. ACTH is produced by the pituitary gland and released into the petrosal
venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH)
from the hypothalamus. ACTH is released in a diurnal pattern that is independent of
circulating cortisol levels: peak release occurs just before awakening, and ACTH levels
then decline throughout the day. Control of CRH and ACTH release is maintained
through negative feedback by cortisol at the hypothalamic and pituitary levels. Neuronal
input at the hypothalamic level can also stimulate CRH release.
Diagnosis
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In pregnant women, the pregnancy may worsen symptoms of Cushing's disease.
The doctor should conduct a thorough physical exam and ask about symptoms
and medical history. In general, the first step in making the diagnosis is establishing a
state of excessive blood cortisol (i.e. Cushing's syndrome). Assuming cortisol intake is
excluded, this typically is done by hormone testing. After this diagnosis is established,
an MRI is obtained to determine if a pituitary tumor is visible.
Tests include:
Hormone testing
Magnetic resonance imaging (MRI) scan
Inferior petrosal sinus sampling
Hormone Testing
The testing for excessive cortisol levels can be complex and challenging. Blood
tests may not detect the presence of excessive cortisol secretion because blood levels
of cortisol naturally vary throughout the day. Therefore a simple measurement of the
blood cortisol level is usually not definitive. Tests we will order include:
In Cushing's disease, the 24-hour urine free cortisol (UFC) levels are typically at
least four to five times greater than normal.
o Your doctor may need two or more elevated 24-hour UFC tests to confirm
the diagnose Cushing's syndrome.
o Uncommonly, Cushing's disease can come and go ("periodic Cushing's
disease"), requiring multiple 24-hour UFC tests.
In some cases, an endocrinologist may request testing for the level of cortisol in
the saliva. Similar to blood cortisol levels, the amount of cortisol in the saliva at or near
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midnight is expected normally to be very low. Multiple elevated midnight salivary cortisol
levels may help confirm the diagnosis of Cushing's syndrome. It is important not brush
the teeth just prior to collecting the sample. This test may not be valid in smokers.
MRI Imaging
Once your doctor suspects Cushing's disease based on clinical findings and
hormonal testing, a magnetic resonance imaging (MRI) scan of the pituitary gland is the
best way to detect the presence of an adenoma in Cushing's disease.
The inferior petrosal sinuses are veins that occur on both sides of the pituitary gland.
Blood leaving the right half of the pituitary gland drains into the right inferior
petrosal sinus and vice versa.
Specially trained interventional neuroradiologists can thread a tiny catheter into
the inferior petrosal sinus. Blood samples are then taken from each sinus and
from a vein just below the heart.
If the ACTH level is the same in the inferior petrosal sinus compared to the vein
below the heart, this suggests that a tumor somewhere else in the body (ectopic, not
pituitary) is producing ACTH.
In Cushing's disease, the ACTH level in the inferior petrosal sinus is much
higher compared to the vein below the heart
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Treatment
Surgery
Medication
Radiation therapy
Other treatment options
Surgically removing the pituitary adenoma offers the only long-term cure of
Cushing's disease.
When an experienced pituitary surgeon performs the operation, the cure rate for
smaller tumors (microadenomas) is 80 percent to 85 percent. If the tumor spread
into nearby internal structures, the cure rate is 50 percent to 55 percent.
Neurosurgeons who specialize in pituitary tumor surgery utilize a technique that
removes the tumor as one piece. They find the tumor and dissect it around the
edge.
The endoscopic endonasal approach is a minimally invasive approach, using
your natural nasal passageway. It does not require a head incision. Our
neurosurgeons have the advanced training and extensive experience necessary
for performing this complex procedure.
An endoscopic technique can be very effective in safely removing tumor, while at
the same time minimizing hospitalization time and discomfort.
There is no effective drug that lowers ACTH production and shrinks the pituitary
tumor. There are medications that inhibit the adrenal gland's production of cortisol. In
some patients, these medications can effectively reduce the symptoms related to
excessive cortisol when:
In some cases, surgeons may not be able to remove the tumor surgically.
Radiation therapy can be very effective in controlling the growth of these tumors.
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Stereotactic radiosurgery is a technique in which a highly focused of radiation can be
delivered to the tumor target. Because the radiation beam is carefully sculpted, the
surrounding brain structures receive only a fraction of the radiation dose and are
typically unharmed (with the exception of the normal pituitary gland).
If the tumor cannot be removed surgically and does not respond to medication or
radiation, your doctor may recommend removing the adrenal glands (bilateral
adrenalectomy), or BLA. If you undergo BLA:
You will need replacement of cortisol with hydrocortisone or prednisone after the
surgery.
You must wear a medical alert bracelet or necklace.
Rapid tumor growth can occur (Nelson's syndrome), since BLA does not affect
the pituitary tumor growth.
Cushing syndrome
Cushing syndrome is a disorder that occurs when your body has a high level of
the hormone cortisol. It is different from Cushing’s disease since Cushing’s disease can
be limited to a rise in cortisol due to pituitary tumors only.
Cushing syndrome is caused by prolonged exposure to elevated levels of either
endogenous glucocorticoids or exogenous glucocorticoids.
Individuals with Cushing syndrome can develop moon facies, facial plethora,
supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae, as shown in
the image below.
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relative adrenal insufficiency should be considered in any patient with Cushing
syndrome.
Skin infections
Purple marks (1/2 inch or more wide) called striae on the skin of the abdomen, thighs,
and breasts
Thin skin with easy bruising
Muscle and bone changes include:
Backache, which occurs with routine activities
Bone pain or tenderness
Collection of fat between the shoulders and above collar bone
Rib and spine fractures caused by thinning of the bones
Weak muscles, especially of the hips and shoulders
Women with Cushing syndrome often have:
Excess hair growth on the face, neck, chest, abdomen, and thighs
Periods that become irregular or stop
CAUSES
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Symptoms of glucocorticoid excess generally occur with the administration of oral
steroids; however, occasionally injections of steroids into joints and the use of steroid
inhalers can cause Cushing syndrome.
Patients with diseases that respond to steroid therapy are especially likely to receive
steroids and thus develop Cushing syndrome. Such disorders include a wide variety of
rheumatologic, pulmonary, neurological, and nephrologic diseases.
Patients who have undergone organ transplants are also at risk for developing
Cushing syndrome due to exogenous steroids required as part of graft antirejection
medication regimens.
Pituitary adenomas that secrete ACTH are derived from corticotrophs in the
anterior pituitary.
ACTH secreted by corticotrophs is released into the circulation and acts on the
adrenal cortex to produce hyperplasia and stimulate the secretion of adrenal
steroids.
Large pituitary adenomas may press on the optic chiasm, causing visual-field
deficiencies that often present as bitemporal field cuts.
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In general, excess androgen secretion is suggestive of an adrenal carcinoma rather
than an adrenal adenoma. These glucocorticoid-producing tumors generally do not
secrete aldosterone, which is produced in the zona glomerulosa layer of the adrenal
cortex.
PATHOPHYSIOLOGY
Urinary free cortisol (UFC) determination has been widely used as an initial
screening tool for Cushing syndrome because it provides measurement of cortisol over
a 24-hour period. A valid result depends on adequate collection of the specimen.
Urinary creatinine excretion can be used to assess the reliability of the collection. Urine
free cortisol values higher than 3-4 times the upper limit of normal are highly suggestive
of Cushing syndrome.
Values higher than the normal reference range but less than 3-4 times the upper
limit of normal are inconclusive. Values that fall within this range may indicate pseudo–
Cushing syndrome or Cushing syndrome and require further testing. Multiple collections
are necessary because patients with disease may have values that fall within the
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normal range. Three urine free cortisol levels in the normal range exclude the diagnosis
of endogenous Cushing syndrome.
The rationale for the dexamethasone suppression tests is based on the normal
physiology of the hypothalamic-pituitary-adrenal axis; glucocorticoids inhibit secretion of
hypothalamic CRH and pituitary ACTH but do not directly affect adrenal cortisol
production. Since cortisol production is controlled by ACTH, decreases in ACTH lead to
decreases in plasma and urine cortisol. The overnight 1-mg dexamethasone
suppression test requires administration of 1 mg of dexamethasone at 11 PM with
subsequent measurement of cortisol level at 8 am.
In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL.
To enhance the sensitivity of the test, a cutoff value of less than 1.8 mcg/dL (50 nmol/L)
excludes Cushing syndrome. Its ease of administration makes the 1-mg
dexamethasone suppression test a widely used screening tool.
Late-night serum and salivary cortisol levels take advantage of the alterations in
circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally,
cortisol values are at their lowest level late at night. In patients with Cushing syndrome,
an elevated serum cortisol at 11 PM can be an early, but not definitive, finding.
Measuring serum cortisol levels requires hospitalization, with blood samples obtained
within 5-10 minutes of waking a patient, and is not a practical test. Measuring salivary
cortisol level has gained interest, as it is a simple and convenient way of obtaining a
nighttime sample. This measurement allows patients to collect their own samples at
home. With repeated measurements, levels less than 1.3 ng/mL (radioimmunoassay) or
1.5 ng/mL (competitive protein-binding assay) exclude Cushing syndrome.
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Less experience has been gathered for this assay, and it is expensive. Most
physicians who do use this test obtain readings over several evenings to increase
accuracy. Results from a meta-analysis of 7 studies relating to late-night salivary
cortisol testing in the diagnosis of Cushing syndrome (947 patients aged >18 years,
including 339 persons with Cushing syndrome) indicated that such testing has a
sensitivity of 92%, a specificity of 96%, and a diagnostic odds ratio of 311. The report's
authors concluded that late-night salivary cortisol measurement "is a robust, convenient
test for screening and diagnosis of Cushing syndrome."
Acute illness activates the HPA axis, resulting in increases in ACTH and cortisol.
The laboratory workup for Cushing syndrome should not be performed when subjects
are acutely ill.
Once the diagnosis is established, the next step requires determining the etiology
of Cushing syndrome. See the flow chart below. The logical first step involves
identifying if the hypercortisolism is an ACTH-dependent or ACTH-independent disorder
Treatment
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Your doctor will instruct you to slowly decrease the medicine dosage. Stopping the
medicine suddenly can be dangerous.
If you cannot stop taking the medicine because of disease, your high blood sugar, high
cholesterol levels, and bone thinning or osteoporosis should be closely monitored.
With Cushing syndrome caused by a pituitary or a tumor that releases ACTH (Cushing
disease), you may need:
Cortisol replacement therapy after surgery and possibly for the rest of your life.
If the tumor cannot be removed, you may need medicines to help block the release of
cortisol.
REFERENCES
1. Burch WM. Endocrinology for the house officer. 3d ed. Baltimore: Williams & Wilkins,
1994:186–9.
7. Stewart PM, Krone NP. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR,
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8. Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA:
Elsevier Saunders; 2011:chap 15.
9. Sharma ST, Nieman LK. Cushing's syndrome: all variants, detection, and
treatment. Endocrinol Metab Clin N Am. 2011;40:379-91. PMID:
21565673 www.ncbi.nlm.nih.gov/pubmed/21565673.
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