Cushing’s syndrome and Cushing’s disease
Definition
Cushing’s syndrome is a condition caused by chronic exposure to elevated levels of the hormone cortisol (hypercortisolism). When a pituitary tumor is the cause of high cortisol, the disorder is called Cushing’s disease.
Causes
Hypercortisolism can result from the use of corticosteroid medications or from overactivity anywhere along the hypothalamic-pituitary-adrenal (HPA) axis.
The HPA axis forms an important connection between the endocrine and nervous systems. It includes a small area of the brain called the hypothalamus; the pituitary gland, which lies just below the hypothalamus; and the adrenal glands, located just above the kidneys.
Through complex feedback mechanisms, neural and chemical signals from the HPA axis regulate the internal environment and help the body adapt or react to various stressors.
The hypothalamus produces CRH (corticotropin-releasing hormone), which stimulates the pituitary gland to produce ACTH (adrenocorticotropic hormone). ACTH then stimulates the adrenal glands to produce cortisol.
Cortisol levels normally vary throughout the day. Blood cortisol is normally high in the morning and low around midnight. This pattern can be disturbed during periods of physical or emotional stress, such as illness, clinical depression, fever, fear, or pain.
Cushing’s syndrome is the result of chronic exposure to high cortisol from any source. Possible causes of high levels of blood cortisol include:
- long-term use of corticosteroid hormones such as cortisone or prednisone
- a tumor or abnormality of the adrenal gland that results in excess cortisol production
- rarely, tumor of the lung, thyroid, kidney, pancreas, or thymus gland that produces hormones to trigger Cushing’s syndrome
- a tumor in the pituitary that causes the adrenal glands to produce too much cortisol (Cushing’s disease)
Cushing’s disease results from a pituitary abnormality that causes the adrenal glands to produce too much cortisol. In most cases, the patient has a pituitary adenoma, a noncancerous tumor, that is producing excessive amounts of ACTH.
Pseudo-Cushing’s syndromes share some of the signs and symptoms of true Cushing’s syndromes. Even some laboratory test results are similar. The likely cause of pseudo-Cushing’s syndromes is overproduction of CRH in the hypothalamus. Alcohol abuse and stressors such as depression, severe obesity, and acute or chronic illness may disturb the HPA axis by prompting the hypothalamus to release excessive amounts of CRH.
Risk factors
A risk factor is something that increases a person’s chances of developing a disease or condition. Risk factors for Cushing’s syndrome include:
- chronic use of corticosteroid medicines (the most common cause of Cushing’s syndrome)
- age 20 to 50 years
- female gender (Cushing’s syndrome is much more common in women.)
Prevention
The only form of Cushing’s syndrome that can be prevented is the type caused by excess corticosteroid medication. Patients who need to take these medications should work closely with their doctor to keep corticosteroid use to the minimum dose needed to treat their condition.
Symptoms
Although symptoms of Cushing’s syndrome and Cushing’s disease vary, some of the most common are:
- weight gain of the upper body and trunk
- moon-shaped face
- skin changes, such as darkening, purple stretch marks, acne, or easy bruising
- in women: excess hair growth and menstrual disorders, especially infrequent or absent periods
- decreased fertility and libido
- high blood pressure
- water retention or swelling
- high blood sugar or diabetes
- tiredness, fatigue
- personality changes, mood swings
- muscle weakness
- osteoporosis
Stunted growth is common in children with Cushing’s syndrome.
Diagnosis
In addition to medical history and physical exam, diagnosis of Cushing’s syndrome or Cushing’s disease requires laboratory studies demonstrating high levels of blood cortisol. Cortisol secretion is directed by ACTH, which is secreted by the front lobe of the pituitary gland and is released in pulses. Thus, serum cortisol shows a daily rhythm as the hormone level rises and falls over the course of the day. A single, one-time blood cortisol level is not a reliable test for hypercortisolism. The “gold standard” has been measurement of 24-hour urinary free cortisol (UFC). Other tests that may be done are the low-dose dexamethasone-suppression test (LDDST) or the late-night salivary cortisol test.
If tests show that cortisol levels are above normal, the reason for this must be identified so that the doctor can determine the best treatment plan. In 80 to 90 percent of patients with hypercortisolism, the pituitary gland is the source of the problem.
Tumor disorders that cause hypercortisolism are characterized not only by excess cortisol production, but also by loss of the normal daily rhythm of cortisol secretion.
Following are some laboratory tests that may be useful in detecting hypercortisolism and in discovering the source.
Tests for hypercortisolism
- 24-hour urinary free cortisol -- Cortisol is excreted in the urine, and overproduction of cortisol is reliably reflected by the 24-hour urinary free cortisol (UFC) test. The test requires the patient to collect and save all urine passed within a 24-hour period.
- Late-night salivary cortisol test -- This is a newer test that is gaining in popularity, partly because specimen collection is painless and easy, even for a child. The patient simply produces and collects a small amount of saliva between 10 and 11 p.m., when cortisol is normally at its lowest level of the day. Because cortisol levels in saliva correspond well with blood cortisol levels, this test is a sensitive and specific tool for detecting hypercortisolism.
Other screening tests for hypercortisolism include the midnight plasma cortisol test and the combined dexamethasone-suppression–corticotrophin-releasing hormone (DS–CRH) test.
If necessary, additional tests can be done to gain information that is more specific. Some of these are listed here.
Low-dose dexamethasone suppression tests
Dexamethasone is a synthetic hormone that is similar to cortisol. Because of the normal HPA axis feedback mechanism, both cortisol and dexamethasone inhibit ACTH secretion (and, therefore, cortisol) in normal people. Therefore, the normal response is lowering of cortisol levels in response to dexamethasone.
The low-dose dexamethasone suppression test (LDDST) is performed either overnight or over a 2-day period.
- Overnight LDDST -- In this test, the patient takes a dose of dexamethasone late at night. In the morning, a fasting blood sample is collected to measure plasma cortisol.
- 2-day LDDST -- For this test, the patient takes a smaller dose of dexamethasone every 6 hours. On the second day, urine is collected for UFC; blood cortisol is measured on the morning after the last dose of dexamethasone and 48 hours after the first dose.
Differential diagnosis of Cushing’s syndrome
If tests indicate hypercortisolism, the next step is to determine the cause. Tests to measure blood ACTH are important in differentiating between Cushing’s disease and other sources of high cortisol.
Cushing’s syndrome is either ACTH-dependent or ACTH-independent. Most cases (80 percent) are ACTH-dependent, and most cases of ACTH-dependent Cushing’s syndrome are due to pituitary tumor (Cushing’s disease). Most patients with ACTH-independent Cushing’s syndrome have an adrenal adenoma. This tumor can usually be detected by either MRI or CT imaging.
Tests to confirm ACTH dependence
ACTH measurement
When hypercortisolism is certain, a plasma ACTH value less than 10 pg/ml establishes ACTH-independent Cushing’s syndrome. Values greater than 20 pg/mL confirm ACTH-dependent Cushing’s syndrome. Plasma ACTH levels between 10 and 20 pg/m are nondiagnostic; an additional test, the CRH-stimulation test, can help clarify the diagnosis.
CRH-stimulation test
The test is performed by obtaining blood for a baseline measurement of ACTH. The patient then receives an injection of CRH, and another blood sample is tested for ACTH.
Patients with Cushing’s disease show a clear increase in blood cortisol and ACTH after receiving CRH. Patients with an ACTH-secreting tumor of the adrenal
This response is not seen in patients whose Cushing’s syndrome is caused by ACTH-secreting adrenal tumors, or most other ectopic (non-pituitary) sources of ACTH. The high-dose dexamethasone-suppression test (HDDST) can help distinguish Cushing’s disease from other ACTH-secreting tumors.
High-dose dexamethasone-suppression test
In the HDDST, dexamethasone is given in a single IV dose, or it can be taken over 2 days or in a single overnight dose. Suppression of cortisol levels by 80 percent or more is very suggestive of ACTH-dependent Cushing’s syndrome, especially Cushing’s disease. However, the HDDST is not specific enough for the test to stand alone in distinguishing between Cushing’s disease and ectopic ACTH-producing tumors.
MRI of the sella turcica
About 60 percent of patients with ACTH-dependent Cushing’s syndrome will show a pituitary adenoma on magnetic resonance imaging of the sella turcica -- an area of the sphenoid bone at the base of the brain. If biochemical tests correlate with Cushing’s disease and the pituitary adenoma measures more than 6mm in diameter, a confident diagnosis of Cushing’s disease is appropriate.
Bilateral inferior petrosal sinus sampling with CRH-stimulation
In this evaluation, the CRH-stimulation test is performed on blood collected by bilateral inferior petrosal sinus sampling (BIPSS). This test is useful for patients with ACTH-dependent Cushing’s syndrome and ambiguous or contradictory clinical, laboratory, or radiological findings. This test is helpful only in patients with a well-established diagnosis of ACTH-dependent Cushing’s syndrome.
In patients with Cushing’s disease, BIPSS can both confirm the diagnosis and help determine whether the tumor is on the left or right side of the pituitary. This is especially important for tumors that are not obvious on MRI.
BIPSS is an invasive procedure. It involves threading a catheter into the right petrosal sinus of the pituitary gland, and another catheter into the left petrosal sinus, from the femoral vein in each side of the groin. Leaving both catheters in place, a small line is placed in an arm vein to collect blood samples. After blood samples are collected from all three sites, the patient is given a dose of CRH. Blood is again collected at timed intervals after CRH is given.
A negative test means that the source of excess ACTH production is not pituitary, or ectopic ACTH production. The BIPSS test cannot identify the source of ectopic ACTH production.
Treatment
Treatment of Cushing’s syndrome depends on the cause. Treatments include:
- surgical removal of the tumor
- radiation for some persistent tumors
- gradual withdrawal of cortisone-type drugs (under close medical supervision)
- drugs to suppress adrenal function
Surgical strategy in Cushing’s disease
When Cushing’s disease is confirmed, surgical resection of the pituitary adenoma that is causing the disease is the best form of treatment.
Classically, a transsphenoidal approach is performed for resection of the presumed ACTH-secreting pituitary adenoma. The pituitary exploration and the tumor resection is performed under direct visualization. The type of the transsphenoidal approach can vary. The technique has evolved over the years. Initially, most operations were performed using a sublabial incision. Subsequently, endonasal hemitransfixion incision or a direct sphenoidotomy with a posterior septal “pushover” technique was used.
We recently adopted the pure endonasal endoscopic approach. The use of the endoscope has consistently improved the quality of ventral skull-base visualization. The endoscope allows for a wide and clear view of sellar structures. The pituitary gland can be well explored under the view of the endoscope.
After the dural incision, the area of the presumed microadenoma seen on MRI is first explored. Next, the remaining pituitary gland is carefully explored for other possible lesions. All tissue deemed abnormal is resected and submitted to pathology.
Hemihypophysectomy (of the side corresponding with either an MRI abnormality or lateralization via inferior petrosal sinus sampling), subtotal hypophysectomy, or total hypophysectomy are more aggressive approaches. These procedures may be performed in cases in which no clearly abnormal tissue is identified during surgery, particularly after a failed first surgery. In general, Total hypophysectomy is reserved for very ill elderly patients.
This content was created by UPMC using EBSCO’s Health Library.