Management of Cushing's Syndrome

Edward M. DeSimone II, RPh, PhD, FAPhA; Paul C. Morales, PharmD; Jarek M. Vetter, PharmD


US Pharmacist 

In This Article


To diagnose CS, a history is obtained and a physical examination is conducted to assess the presenting signs and symptoms. There are currently two first-line screening tests for CS, with a third screening test currently being validated. The first-line screening tools are the 24-hour urinary free cortisol (UFC) test and the low-dose dexamethasone suppression test (DST).[7]

Confirmation of CS

UFC Test: UFC levels correlate with free plasma levels of cortisol. The patient collects three 24-hour samples of urine for analysis.[10] Normal urine cortisol tests are under 100 mcg/24 h.[11] A result that is four times the upper limit of normal (typically 440 mcg/24 h), which is rare, indicates CS.[10] The UFC test is not indicated in patients with renal impairment—defined as a glomerular filtration rate less than 30 mL/min—because of decreased cortisol excretion. The screening sensitivity does not allow for the detection of subclinical or preclinical CS.

DST: In healthy patients, dexamethasone suppresses plasma cortisol levels. In CS, this mechanism can be overridden by the underlying disease. For the DST, the patient is administered 1 mg dexamethasone between 2300 and 2400 hours. The following morning, cortisol concentration levels are measured. A measurement above 5 mcg/dL indicates inhibition of a negative feedback loop, as seen in CS. While a level of 1.8 mcg/dL allows for identification of pseudo-CS, cyclic CS, or early stages of CS, it also may create false-positive results.[12] A two-day 2-mg DST may be used in clinical practice; however, cost and increased hospitalization are limiting factors in its use.

Late-Night Salivary Cortisol Test (LST): LST is a new screening tool being evaluated for CS. Salivary cortisol concentration is closely related to free plasma, but it remains independent of salivary flow rate. Normal ranges for this screening are assay-dependent. Current studies suggest high specificity and sensitivity, but further research is needed to validate the use of LST as a screening tool.[10]

Differential Diagnosis

Once CS is diagnosed, further testing is necessary to differentiate the cause, thereby enabling proper treatment. Current second-line tests are ACTH measurement, high-dose DST, and the CRH stimulation test (TABLE 1).[10] All patients with ACTH-dependent CS should undergo pituitary MRI. The bilateral inferior petrosal sinus sampling (BIPSS) test samples blood surrounding the pituitary, allowing for accurate diagnosis of pituitary origin of high ACTH. BIPSS also is recommended in patients with ACTH-dependent CS. However, owing to rare but significant complications, the risks and benefits need to be taken into consideration. BIPSS has a sensitivity of 95% to 99% when performed at "experienced centers."[10] Several new differential diagnosis tests are currently being researched, including one involving the use of desmopressin.[10]

Complications of CS

Accurate treatment of CS is important in order to avoid the numerous complications that can stem from disease progression. Major cardiovascular complications are hypertension, impaired glucose tolerance, obesity, hyperlipidemia, hypercoagulability, metabolic syndrome, and osteoporosis. Psychiatric complications such as psychosis, mania, suicidal tendency, obsessive-compulsive disorder, cognition changes, and anxiety also may develop. Last, high cortisol levels may create alterations in other areas of the endocrine system, such as the somatotrophic axis (which can decrease growth rate in younger patients or alter fat distribution in adults), the gonadal axis (which can have adverse effects on reproductive organs), and the thyroid axis (which can lead to hypothyroidism or hyperthyroidism). These complications may persist even if a patient has subclinical CS.[10]


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