GROUP

C2
Physiology Laboratory
Small Group Discussion
Output

April 13, 2016

[CUSHING’S DISEASE &

SYNDROME]
By: ASUBARIO, Olufunmilola Omonike; BALADAD, Alvin Bryan; DE JESUS, Chrislou; GURUNG, Man
Bahadur; KALANGEG, Kristie; MAHALEE, Naphitcharak; MONTHATHONG, Thanapol; PANLASIGUI,
Rikkimae Maria; SAMSON, Chino Paolo; SOLONIO, Natalie Keith; VALDEZ, Gregorio
 Cushing's Disease

Cushing's disease is a serious condition of an excess of the steroid hormone

cortisol in the blood level caused by a pituitary tumor secreting adrenocorticotropic
hormone (ACTH). ACTH is a hormone produced by the normal pituitary gland. ACTH
stimulates the adrenal glands (located on top of the kidneys) to produce cortisol,
commonly referred to as the stress hormone.

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.

Most patients with Cushing's disease have small tumors (pituitary

microadenomas). However, it can be difficult to diagnosis Cushing's disease, and the
diagnosis is often delayed. An endocrinologist should always supervise the evaluation
for Cushing's disease. At the UCLA Pituitary Tumor Program, our specialists have years
of experience diagnosing and managing Cushing's disease.

Cushing's Disease vs. Cushing's Syndrome

Cushing's disease is not the same as Cushing's syndrome. Cushing's syndrome

refers to the general state characterized by excessive levels of cortisol in the blood.
Elevated cortisol levels can occur for reasons other than a pituitary tumor, including:

 Tumors of the adrenal glands producing cortisol

 Certain types of cancer, elsewhere in the body, can make ACTH, which then
stimulates the normal adrenal glands to make excessive cortisol. This is called
ectopic ACTH production.

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

Less common causes of elevated cortisol levels:

 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.

Cushing's disease is used exclusively to describe the condition of excessive cortisol

arising from a pituitary tumor secreting the hormone ACTH.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 1
Symptoms

The symptoms related to Cushing's disease and

Cushing's syndrome are the same, since both are
related to an excess of cortisol. The symptoms
may include:

 Changes in physical characteristics of the

body
o Fullness and rounding of the face (so-
called "moon facies")
o Added fat on back of neck (so-called "buffalo hump")
o Easy bruising of the skin
o Purplish stretch marks on the
abdomen (abdominal striae)
o Excessive weight gain, most marked
in the abdominal region, while the
legs and arms remain thin
o Red cheeks ("plethora")
o Excess hair growth on the face, neck,
chest, abdomen and thighs

 Generalized weakness and fatigue; wasting

of muscles, most noticeably in the upper thighs. You may have difficulty getting
up from a chair.
 Menstrual disorders
 Decreased fertility and/or sex drive
 High blood pressure that is often difficult to
treat
 Diabetes mellitus, often severe
 Mood and behavior disorders; some patients
have psychiatric disorders that require
hospitalization

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

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 2
 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.

The role of corticosteroid medications

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.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 3
 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.

It's also possible to develop Cushing syndrome from injectable corticosteroids —

for example, repeated injections for joint pain, bursitis and back pain. Inhaled steroid
medicines (taken for asthma) and steroid skin creams (used for skin disorders such as
eczema) are generally less likely to cause Cushing syndrome than oral corticosteroids.
But, in some individuals, these medications may cause Cushing syndrome, especially if
taken in high doses.

Your body's own overproduction

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:

 A pituitary gland tumor (pituitary adenoma). A noncancerous (benign) tumor of

the pituitary gland, located at the base of the brain, secretes an excess amount of
ACTH, which in turn stimulates the adrenal glands to make more cortisol. When
this form of the syndrome develops, it's called Cushing disease. It occurs much
more often in women and is the most common form of endogenous Cushing
syndrome.

 An ectopic ACTH-secreting tumor. Rarely, when a tumor develops in an organ

that normally does not produce ACTH, the tumor will begin to secrete this hormone
in excess, resulting in Cushing syndrome. These tumors, which can be
noncancerous (benign) or cancerous (malignant), are usually found in the lungs,
pancreas, thyroid or thymus gland.

 A primary adrenal gland disease. In some people, the cause of Cushing

syndrome is excess cortisol secretion that doesn't depend on stimulation from

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 4
 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.

 Familial Cushing syndrome. Rarely, people inherit a tendency to develop tumors

on one or more of their endocrine glands, affecting cortisol levels and causing
Cushing syndrome.

Pathophysiology of Cushing's Disease

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.

Although the adenomas of Cushing's disease secrete excessive amounts of

ACTH, they generally retain some negative feedback responsiveness to high doses of
glucocorticoids. Ectopic sources of ACTH, usually in the form of extracranial neoplasms,
are generally not responsive to negative feedback with high doses of glucocorticoids.
However, some overlap exists in the response to negative feedback between pituitary
and ectopic sources of excessive ACTH.

Diagnosis

The early stages of Cushing's disease may be difficult to recognize, especially

because the body changes develop slowly. Comparing old and recent photographs
often shows the changes in facial appearance and physical characteristics of the body.

The diagnosis may be difficult to make because sometimes the hormone

elevations come and go: so called "cyclic" or "periodic" Cushing's disease.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 5
 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.

In Cushing's disease, typically very small (microadenoma) tumors are found. If no

tumor is visible, then inferior petrosal sinus sampling is indicated (see below).

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:

 24-hour urine free cortisol (UFC) measurement

 Cortisol saliva testing
 Blood ACTH
o If low, may suggest the presence of an adrenal tumor producing cortisol

24-hour urine free cortisol (UFC) measurement

The amount of cortisol found in urine collected over a 24-hour period is an

important measurement in diagnosing Cushing's syndrome. This test sums the total
daily production of cortisol.

 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.

Cortisol saliva testing

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
Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 6
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.

MRI detects a pituitary adenoma in about 70 percent of cases. It is important that

you undergo these imaging tests at a Pituitary center with special expertise in imaging
small tumors. At the UCLA Pituitary Tumor Program, we use powerful 3T (Tesla) MRI
scanners that may offer improved chances of identifying very small tumors.
At UCLA, our neuroradiologist personally oversees the MRI scan as it is being acquired
in order to perform the optimal scanning sequences to detect tiny pituitary tumors not
seen elsewhere.

Inferior petrosal sinus sampling

In some cases, MRI fails to identify an abnormality. If your doctor suspects

Cushing's disease, he or she may order super-selective inferior petrosal sinus sampling
(IPSS).

IPSS must be performed by an experienced interventional neuroradiologist

because it carries risk, and if done inappropriately, can give misleading results.

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

If IPSS testing is not available, other tests include a dexamethasone suppression

test. Dexamethasone is a powerful drug that acts similar to, but is more potent than
cortisol. This type of testing can suggest either a pituitary or ectopic tumor, but is not as
conclusive as IPSS.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 7
Treatment

Treating Cushing's disease requires an experienced team of experts. To achieve the

best outcome, you should seek treatment at a hospital that has a dedicated pituitary
tumor program.

Treatment options include:

 Surgery
 Medication
 Radiation therapy
 Other treatment options

Surgery for Cushing's Disease

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.

Medical Therapy for Cushing's Disease

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:

 Surgery fails to completely remove the tumor.

 Medication is necessary before surgery, in a patient who is very ill.

Radiation Therapy for Cushing's Disease

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.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 8
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).

A consequence of radiation treatment is that it can cause delayed pituitary

failure. This typically occurs several years after treatment, and therefore continued long-
term follow-up with an endocrinologist is important. Hormone replacement may be
required.

Other Treatment Options

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.

Individuals often complain of proximal muscle weakness, easy bruising, weight

gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes
mellitus, and impaired immune function may occur.

In an emergency situation, remembering that the most common cause of

Cushing syndrome is the use of exogenous glucocorticoids is important. Exogenous
steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that
can last for as long as a year after exogenous steroid administration has ended.

An individual with HPA-axis suppression cannot increase steroid production

appropriately during a medical illness or other stress and would need to receive stress
doses of steroids to avoid adrenal crisis. Thus, in an emergency, the potential for

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 9
 relative adrenal insufficiency should be considered in any patient with Cushing
syndrome.

Signs and Symptoms

Most people with Cushing syndrome will have:

 Round, red, full face (moon face)

 Slow growth rate in children
 Weight gain with fat accumulation on the trunk, but fat loss from the arms, legs, and
buttocks (central obesity)

Skin changes that are often seen:

 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

Men may have:

 Decreased or no desire for sex

 Impotence
Other symptoms that may occur with this disease:
 Mental changes, such as depression, anxiety, or changes in behavior
 Fatigue
 Headache
 Increased thirst and urination

CAUSES

1. Exogenous steroid administration

 Administration of exogenous steroids may lead to the development of Cushing

syndrome.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 10
 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.

2. Endogenous glucocorticoid overproduction

 ACTH-producing pituitary adenoma

 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.

 These adenomas, if large, can result in loss of production of other anterior

pituitary hormones (TSH, FSH, LH, growth hormone, and prolactin) and the
posterior pituitary hormone vasopressin.

 Pituitary tumors can also compress the hypophyseal stalk leading to

hyperprolactinemia from loss of dopamine inhibition.

 Nelson syndrome is caused by a large ACTH-secreting pituitary tumor; it is often

locally invasive, difficult to cure, and associated with hyperpigmentation. In
patients who undergo adrenalectomy without pituitary irradiation, the incidence of
Nelson syndrome is about 20-25%.

 Large pituitary adenomas may press on the optic chiasm, causing visual-field
deficiencies that often present as bitemporal field cuts.

3. Primary adrenal lesions

 Overproduction of glucocorticoids may be due to an adrenal adenoma, adrenal

carcinoma, or macronodular or micronodular adrenal hyperplasia. The zona
fasciculata and zona reticularis layers of the adrenal cortex normally produce
glucocorticoids and androgens. Glucocorticoid-secreting tumors are derived from
these cells and, thus, may secrete both glucocorticoids and androgens.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 11
 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.

 The Carney complex is a familial form of micronodular hyperplasia of the adrenal

gland. It is an autosomal dominant disorder and ACTH independent cause of
Cushing syndrome. Pigmented skin lesions and mesenchymal and endocrine tumors
characterize the disorder. Cushing syndrome may be overt, subclinical, cyclical, or
periodic.

 McCune-Albright syndrome is a rare cause of precocious puberty. It is associated

with hyperfunction of the adrenal glands that may lead to Cushing syndrome.

4. Ectopic ACTH is sometimes secreted by oat cell or small-cell lung tumors or by

carcinoid tumors.

PATHOPHYSIOLOGY

Excess levels of either exogenously administered glucocorticoids or endogenous

overproduction of cortisol causes Cushing syndrome. Endogenous glucocorticoid
overproduction or hypercortisolism that is independent of ACTH is usually due to a
primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral
micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing
syndrome.

ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. They

usually are due to an anterior pituitary tumor, that is, classic Cushing disease (80%).
Nonpituitary ectopic sources of ACTH, such as an oat cell carcinoma, small-cell lung
carcinoma, or carcinoid tumor, cause the balance of ACTH-dependent disease. Ectopic
corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion
comprise a very rare group of cases of Cushing syndrome

Diagnosis of Cushing syndrome

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

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 12
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.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 13
 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."

The dexamethasone-CRH test is intended to distinguish patients with Cushing

syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose
dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg every
6 hours) is given 8 times starting at about 8 AM, CRH is administered intravenously 6
hours after the last dose of dexamethasone and plasma cortisol andACTH levels are
obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4
mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical
suspicion for Cushing syndrome but equivocal results on other diagnostic tests.
Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal
cortisol secretion or pseudo-Cushing states. The aforementioned tests can produce
both false-positive and false-negative results. False-positive results are associated
with obesity, alcoholism, chronic renal failure, affective disorders, strenuous exercise, or
eating disorders. Other potential confounders in the interpretation of tests include the
following:

 Medications that increase corticosteroid-binding globulin, such as estrogen and

tamoxifen, may cause appropriate increases in serum cortisol levels.
 Medications that facilitate the metabolism of dexamethasone, such as phenobarbital,
phenytoin, and rifampin, may cause false-positive results with the dexamethasone
suppression test.

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

Treatment depends on the cause.

Cushing syndrome caused by corticosteroid use:

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 14
 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:

 Surgery to remove the tumor.

 Radiation after removal of a pituitary tumor in some cases.

 Cortisol replacement therapy after surgery and possibly for the rest of your life.

With Cushing syndrome due to an adrenal tumor or other tumors:

 You may need surgery to remove the tumor.

 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.

2. Carpenter PC. Cushing's syndrome: update of diagnosis and management. Mayo

Clinic Proc. 1986;61:49–58.

3. Orth DN. Cushing's syndrome. N Engl J Med. 1995;332:791–803 [Published erratum

appears in N Engl J Med 1995;332:1527]

4. Meier CA, Biller BM. Clinical and biochemical evaluation of Cushing's

syndrome. Endocrinol Metab Clin North Am. 1997;26:741–62.

5. Tsigos C, Chrousos GP. Differential diagnosis and management of Cushing's

syndrome. Annu Rev Med. 1996;47:443–61.

6. McGee S. Cushing syndrome. In: Evidence-Based Physical Diagnosis. 3rd ed.

Philadelphia, PA: Elsevier Saunders. 2012:chap 13.

7. Stewart PM, Krone NP. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR,

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 15
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.

Physiology Laboratory Small Group Discussion Output | Cushing’s Disease & Syndrome 16