Cushing Syndrome

The signs and symptoms of Cushing Syndrome are the results of cortisol levels that are abnormally high, which is referred to as hypercortisolism. Cortisol is a steroidal hormone that is produced by the cortex, which is the outer layer of the adrenal gland.

The hormone has multiple functions, including: 

• The break-down of fat. 
• Encourages glucose production in the liver. 
• Assists in the reaction to emotional and physical stress. 
• Regulates blood pressure. 
• Controls inflammation. 
• Affects the function of the cardiovascular system. 

The adrenal glands, located at the apex of each kidney, form part of the endocrine system, which is a network of glands in the body that are responsible for the production of hormones. The adrenal cortex is specifically tasked with the production of cortisol, aldosterone as well as adrenal androgens (mainly dehydroepiandrosterone or DHEA). 

A feedback system revolving around the pituitary gland, the adrenal glands and the hypothalamus (a gland located in the lower brain) is responsible for regulating cortisol production. When the hypothalamus detects low levels of cortisol, it produces corticotropin-releasing hormones or CRH. This hormone stimulates the production of adrenocorticotropic hormones or ACTH in the pituitary gland. This hormone, also referred to as corticotropin, in turn, stimulates the production and release of cortisol in the adrenal glands. High levels of cortisol reduce the production of CRH and ACTH to suppress cortisol production. 

Common Causes of Cushing Syndrome 

• Extended glucocorticoid treatment resulting in iatrogenic Cushing Syndrome. Glucocorticoids are synthetic steroids that mimic cortisol on a chemical basis like Prednisone, which is used to treat health conditions such as asthma, rheumatoid arthritis, lupus, and other diseases that are inflammatory in nature. These hormones may also be prescribed after organ transplants to prevent organ rejection by lowering the immune system. 
• Cushing’s Disease, which is a type of Cushing Syndrome, results from the overproduction of ACTH by the pituitary gland, which continuously signals the adrenal glands to produce excess endogenous cortisol. Most commonly, Cushing’s Disease, which makes up 40% of cases, is the result of a tumor called an adenoma on the pituitary gland that secretes ACTH. 
• A tumor on the adrenal gland called adrenal hyperplasia, which causes excess production of cortisol.  
• Tumors in other parts of the body, such as the thyroid, pancreas, or lungs that produce ACTH. This is referred to as the ectopic production of ACTH as it is produced in parts of the body other than the pituitary gland. 
• Gene mutations that are inherited like Multiple Endocrine Neoplasia Type 1 (MEN-1) increases the risk of tumor development in the endocrine system, including the adrenal and pituitary glands. These genetic conditions are, however, rare in causing Cushing Syndrome. 
• Obesity and the development of Type II Diabetes or those who have poorly regulated blood glucose levels are at a greater risk of developing Cushing Syndrome. 

Cushing Syndrome may develop in any person. However, it is more frequently seen in adults between 20 and 50 years of age, and women are three times more likely to develop the condition than men. An estimated two new cases per million people are diagnosed every year.  

Signs and Symptoms of Cushing Syndrome 

The multiple signs and symptoms of Cushing Syndrome may vary but commonly include: 

• Central obesity or obesity in the torso with thinner arms and legs. 
• “Moon face” or the appearance of a large, rounded face. 
• “Buffalo hump,” which refers to excessive fat in the neck and shoulder area. 
• Excessive urination and thirst. 
• Vision conditions, such as glaucoma and cataracts. 
• Greater susceptibility to infection. 
• Thin, fragile skin that heals slowly and is prone to bruising. 
• Pink streaks, like stretch marks in the abdomen, buttocks, and thighs. 
• Weakness of the muscles. 
• Reduced endurance. 
• Decreased bone density or osteoporosis. 
• Mental health conditions, such as confusion and psychosis. 
• Children who have Cushing Syndrome develop slower than normal, are shorter in height, and are commonly obese. 
• Women may grow excess hair on the face and chest and have irregular menstruation. 
• Men may be impotent or lack sex drive. 

Laboratory Testing for Cushing Syndrome 

A single laboratory test is insufficient to diagnose Cushing Syndrome, and more than one test is the standard. Cortisol levels vary throughout the day, meaning that a singular blood sample for cortisol is not accurate. Testing is, therefore, conducted in two stages. Initial testing is to determine whether increased levels of cortisol are present. The second phase of testing is to identify the cause of the increase in cortisol levels, whether this is due to adrenal, pituitary, or other causes.

Three tests are commonly used to diagnose Cushing Syndrome: 

• Measurement of midnight plasma cortisol and late-night salivary cortisol. Commonly, cortisol production is reduced at midnight. With Cushing Syndrome, this does not happen, and an increased cortisol level in the blood or plasma at this time may indicate the condition. The blood test usually requires admission to the hospital for at least one night. The alternative is to collect a saliva sample at home, late at night, to be submitted for later testing. The recommendation is for saliva samples to be collected over three consecutive nights. In the case where a single saliva sample was tested, and the results are outside the established range of reference, the test should be repeated in order to eliminate a false-positive. 
• 24-Hour urine cortisol test (or the urine free cortisol test or UFC) is generally performed to measure overall cortisol production. When one out of four samples tested within a 24-hour period is normal, or the overall results are abnormal, further testing may be required, such as the midnight plasma cortisol test in order to prevent a false-positive. 
• Dexamethasone suppression screening test (DSS test) which introduces synthetic cortisol to evaluate the production of CRH and ACTH production. The normal response to the introduction of dexamethasone would be a suppression of the hormones CRH, ACTH, and cortisol. The test can be administered in different dosage at various times of the day.  

A low dose of 1mg can be administered at night in order to reduce the increase of ACTH and cortisol that are normally produced during sleep. A blood sample drawn the morning after will then be measured to detect cortisol levels. Cushing syndrome will prevent the suppression of this production, whereas healthy individuals will show a marked suppression in the production of ACTH and cortisol. 

Alternatively, 0.5mg can be administered every six hours over a period of 48 hours and a 24-hour urine sample collected on the second day for urine free cortisol testing. The urine free cortisol test should show suppression to extremely low levels in healthy individuals and high levels in persons with Cushing Syndrome. 

If any of the above tests show increased levels of cortisol, then it is a clear indication that cortisol levels are not being regulated normally. The second phase of testing to determine the cause of the increased levels of cortisol will then be ordered. 

Testing to Establish the Cause of Cushing Syndrome:

• Corticotrophin releasing hormone (CRH) stimulation test is used to distinguish between individuals who have a pituitary gland condition and those with tumors existing outside of the pituitary gland and are responsible for producing ectopic ACTH. Baseline ACTH levels are measured before CRH is injected. Cortisol and ACTH levels are then measured at either 30 minutes or 1-hour timed intervals. Normal responses to this test should first show an increase in ACTH levels and then a peak in cortisol levels. Cushing Syndrome caused by adrenal tumors or tumors producing ACTH will show no response to the injected CRH. 
• High-dose dexamethasone suppression test (HDDST) is like the lower dose version used to detect irregular cortisol levels in the initial phase of testing. The test is administered to distinguish between pituitary tumors producing ACTH and the other causes of Cushing Syndrome. The high dose of dexamethasone should suppress cortisol levels in those with pituitary tumors but not in persons where the cause is a tumor producing ectopic ACTH. 
• Dexamethasone-corticotropin-releasing hormone test is to differentiate between Cushing Syndrome and pseudo-Cushing syndrome. Pseudo-Cushing Syndrome is where cortisone levels are elevated, but the long-term, progressive symptoms and signs are not in evidence. Excessive alcohol consumption, severe obesity, unmanaged diabetes as well as depression and anxiety can all result in higher cortisol levels, but symptoms such as muscle weakness, osteoporosis, or fragile skin may not be present. The test is a combination of the dexamethasone test and the CRH test mentioned above. Elevated levels of cortisol suggest Cushing Syndrome, whereas levels that do not increase suggest pseudo-Cushing Syndrome. 
• Petrosal sinus sampling is commonly used in conjunction with the CRH stimulation test. Blood samples are obtained from the petrosal sinuses, which are veins that carry blood from the pituitary gland. The samples are collected from a catheter placed in the neck and used to measure ACTH levels. Cortisol levels are then compared with those of blood that is taken from the forearm. ACTH levels that are higher in the blood obtained from petrosal sinuses are indicative of a pituitary tumor. If the levels are similar in both samples, it indicates that the increased levels of cortisol are caused by a tumor other than on the pituitary gland. 

Additional Lab Tests for Cushing Syndrome 

CBC differential to measure high levels of WBC and a greater number of neutrophils. 

A glucose tolerance test to measure impairment. 

Testing for hypokalemia which is a decreased level of potassium.