Cushing's Syndrome

Cushing's syndrome is a disorder that is caused when the body is exposed to an excess amount of cortisol. All of the organs and tissues in the body can be affected by cortisol. The effects created are Cushing’s syndrome.

This disorder can be caused from cortisol medication overuse. This is seen in the treatment of chronic asthma or rheumatoid arthritis (iatrogenic Cushing's syndrome), a tumor that produces excess cortisol (ectopic Cushing's syndrome), or a tumor of the pituitary gland secreting adrenocorticotropic hormone (ACTH) which creates excess cortisone from the adrenal gland (Cushing’s disease).

Cortisol is a hormone produced in the adrenal glands. Cortisol is needed by the body to rescind to stress and change. It will transport nutrients, modify the body's inflammatory response, stimulate the liver to increase blood sugar levels and control water levels in the body. The production of cortisol is controlled by the ACTH made in the pituitary gland.

PREVALENCE OF CUSHING'S SYNDROME

• Around 10-15 million people affected every year
• Cushing’s disease or pituitary adenomas make up 70% of cases in adults and 60-70% in children
• More prevalent in females (70% of all cases)
• Typically affects ages 20-50 years old

UNDERLYING CAUSES

Pituitary Adenoma - Cushing's Disease

Pituitary adenomas are benign tumors of the pituitary gland that cause too much cortisol production by secreting increasing amounts of ACTH. Majority of patients will have a single adenoma. Cushing’s disease is the most frequent cause of spontaneous Cushing’s syndrome, making up 60-70% of cases.

Ectopic ACTH Syndrome

Sometimes benign or malignant tumors that appear outside the pituitary gland can make ACTH. This is called ectopic ACTH syndrome. Lung tumors make up over 50% of these cases. Other tumors that can make ACTH are thymomas, pancreatic islet cell tumors and medullary carcinomas of the thyroid.

Adrenal tumors

Issues that arise in the adrenal glands, for instance an adrenal tumor, could lead to cushing's syndrome. The majority of these cases release excess cortisol into the blood due to benign adrenal adenomas.

A very uncommon cause of Cushing’s syndrome is adrenocortical carcinomas (adrenal cancers). Cancel cells secrete excess levels of multiple adrenal cortical hormones that include cortisol and adrenal androgens. Adrenocortical carcinomas usually lead to extremely high levels of hormones and a very fast arisal of symptoms.

Familial Cushing’s Syndrome

Usually Cushing’s syndrome is not genetic. Some families may have a higher likelihood of developing tumors to the endocrine glands and so they are more likely to develop Cushing’s syndrome. Children or young adults with primary pigmented micronodular adrenal disease may develop small tumors of the adrenal glands that produce cortisol. In multiple endocrine neoplasia type 1 (MEN I), tumors that secrete hormones of the parathyroid gland, pancreas and pituitary gland may arise. Cushing’s syndrome in MEN I can be caused by a pituitary, ectopic, or adrenal tumor. 

SIGNS AND SYMPTOMS OF CUSHING’S SYNDROME/DISEASE

• Weight gain in face
• Weight gain above collar bone (supraclavicular fat pad)
• Weight gain on the back of the neck (buffalo hump)
• Skin changes with easy bruising
• Purple colored stretch marks over abdomen or axillary area
• Red and round face (plethora)
• Weight gain centered over chest and abdomen while arms and legs are thin
• Hair growth on face, chest, abdomen, thigh, in excess
• Female balding
• Weakness or fatigue
• Blurred vision
• Vertigo
• Muscle weakness
• Amenorrhea in women
• Decreased fertility or sex drive
• Hypertension
• Poor wound healing
• Diabetes mellitus
• Depression
• Moody

DIAGNOSIS

The diagnosis of Cushing’s syndrome will be based on clinical suspicion, patients medical history, exams, testing, cortisol levels. A patient who might have Cushing’s syndrome must have excess cortisol levels with an increase in urinary excretion of cortisol for 24 hours. Look at changes in body and facial appearances.

These tests can assist in determining if excessive levels of cortisol is being made:

• 24 hours urinary cortisol test: measures cortisol amount produced in urine over 24 hours. Levels that are higher than 50-100 micrograms a day in adults shows a possibility of Cushing's syndrome. Mild cases of Cushing’s syndrome may not have a change in cortisol levels so many 24 hour urine tests should be taken.
• Low-dose dexamethasone suppression test: Measures adrenal gland’s response to ACTH. Taking a small dosage of a drug similar to cortisol, dexamethasone (1mg), at 11 p.m., then having blood drawn the next morning to screen for cortisol. If a patient does not have Cushing’s syndrome, the cortisol level will be low which means that ACTH secretion was suppressed by the dexamethasone dose. If a patient has Cushing’s syndrome, the cortisol level in the morning will be high. This shows that they do not suppress cortisol to a low level (2.8 mg/dl). This test is around 95-97% accurate. Mild cases of Cushing’s syndrome can sometimes suppress their cortisol levels to low levels which makes it very difficult to diagnose.
• Late night salivary cortisol test: This is a newer test checking for cortisol level around 11 p.m. to midnight. It is done at this time since cortisol secretion is quite low during this time of night. But, patients with Cushing’s syndrome will not have low cortisol secretion at this time. This test can be done multiple times and is easy to perform. This test is 93-100% accurate to come to a diagnosis.

After a diagnosis is made, the source of the syndrome must be found. This is done first by looking at the measurement of ACTH. If the patient has an ACTH-secreting tumor, they will have normal to high levels of ACTH. Patients with an excess of adrenal cortisol will have below normal levels of ACTH. A high-dose dexamethasone suppression test is also useful. Patients with pituitary tumors may suppress their serum cortisol level but those with adrenal tumors can maintain a higher level of cortisol. If the levels of cortisol are high, this leads the doctor in the direction of a non-pituitary source. Figuring out a pituitary from a non-pituitary ACTH-secreting tumor is difficult. MOst patients with ACTH-secreting tumors have a pituitary lesion that is small. 

Here are some other recommended tests:

• Magnetic Resonance Imaging (MRI) of the pituitary gland with gadolinium enhancement. An obvious pituitary tumor can be seen with an MRI. 50% of patients will have a normal MRI of the pituitary while 10% will have incidental tumors that are not related to ACTH production.
• Petrosal sinus sampling can be done to see the source of ACTH secretion. This test should be done after Cushing’s syndrome is confirmed. ACTH and other pituitary hormones produced in the pituitary gland will enter the bloodstream by drainage through the inferior petrosal sinuses. A catheter is placed in the inferior petrosal sinuses at the same time and blood is checked for ACTH before and after the administration of the corticotropin-releasing hormone (CRH) and at two, five, and ten minute intervals. This test is a 95-98% diagnostic accuracy when done correctly.

TREATMENT OF CUSHING’S SYNDROME

Treatment will vary patient by patient but treatment can include surgery, radiation, chemotherapy, or cortisol-inhibiting drugs. If the cause is iatrogenic, caused by the use of glucocorticoid hormones over time to treat another disorder, the physician will slowly decrease the dose of externally administered steroid to the lowest dose possible to control that disorder. Once under control, the dose of glucocorticoid hormones can be given on alternating days to reduce the patient;s side effects.

In patients to whom a remission is not received after surgery, here are medications that can be used to inhibit cortisol production:

• Ketoconazole (Nizoral)
• Mitotane (Lysondren)
• Metyrapone (Metopirone)
• Mifepristone (Korlym)

These are not as effective as a surgical approach and are only a second line course of treatment. Some patients may be resistant to all forms of therapy and in this case, the bilateral removal of the adrenal glands could be considered.

After surgery, if the tumor removal is a success, ACTH levels will drop below normal. This is normal and temporary. Patients can be prescribed a synthetic form of hydrocortisone or prednisone. The majority of patients can stop replacement therapy between six or 12 months but some may require it for years or life. Those who need adrenal surgery may also need steroid replacement surgery.

Patients who are not able to get surgery may consider radiation therapy. This is administered over six weeks to the pituitary gland has shown a 40-50% improvement in adults and early 85% improvement in children.

Patients with ACTH-secreting pituitary adenomas have found stereotactic radiosurgery helpful. A study has shown endocrine remission in 54% of patients and tumor growth control in 96% of patients. It is important to observe for tumor growth, disease recurrence, hormone deficiencies and damage to optic nerves and brain.