Cushing Syndrome

The adrenal gland is a triangular-shaped gland that sits on top of each kidney. Cortisol is one of the key hormones in our body and is made by the adrenal gland. Cortisol production is regulated by multiple steps in the brain. A part of the brain called the hypothalamus makes a hormone called ‘CRH.’ CRH tells the pituitary gland (the master gland in the brain) to make another hormone called ACTH. ACTH then directs the adrenal gland to make cortisol.

CRH ⇋ ACTH ⇋ Cortisol

Cortisol is important because it regulates our blood pressure, and metabolism and helps us deal with physical stress. Cushing syndrome occurs because of excess exposure to cortisol. If someone is given cortisol (cortisone or prednisone or dexamethasone preparations) for extended periods, this can result in ‘Exogenous Cushing Syndrome.’ When excessive cortisol levels are because of overproduction within the body, it is called ‘Endogenous Cushing Syndrome.’ The overproduction of cortisol can be from a tiny pituitary tumor or microadenoma (70% of the cases) or benign adrenal tumors known as adrenal adenomas. Some tumors that develop outside the pituitary gland (e.g. pancreas, thymus, lungs) can also produce ACTH.  This condition is called ectopic ACTH-dependent Cushing syndrome and is less common. 

Cushing syndrome is an uncommon condition (40-70 persons/million) but results in serious health problems and can be fatal if untreated. Complications related to Cushing syndrome may include:

  • progressive and rapid weight gain
  • type 2 diabetes which may be difficult to control
  • high blood pressure, which is difficult to control 
  • blood clots 
  • premature heart disease (e.g. heart attack or stroke) 
  • recurrent infections 
  • osteoporosis 

Cushing syndrome is associated with certain signs on physical exams. Some of these signs are non-specific such as obesity or high blood pressure. Other signs are more characteristic of Cushing syndrome such as:  

  • weight gain in the central part of the body with relatively thin arms and legs
  • skin becoming thin over the arms or legs
  • round face with facial redness 
  • increased fat around the back of the neck  
  • easy bruising
  • wide and purple or red/pink colored stretch marks on the abdomen  
  • increased facial hair
  • male pattern baldness
  • muscle weakness. 

How is Cushing Syndrome diagnosed?

Diagnosis of Cushing syndrome relies on clinical features and certain laboratory tests. Your doctors may order urine, saliva, or blood tests to diagnose Cushing syndrome. Tests are not always conclusive and repeat testing is often needed. Measuring a random blood level of cortisol is not useful because pain or anxiety from the needle stick can cause elevated blood cortisol levels.  

Blood cortisol levels fluctuate throughout the day depending on stress levels. In addition, in normal people, blood cortisol levels drop to a very low level in the evening and around midnight, but this does not occur in those with Cushing syndrome.  Since obtaining blood samples is difficult late at night, a saliva specimen can be collected at home around 11 pm. Saliva cortisol levels done by major commercial labs (e.g. Quest Diagnostics or LabCorp) are quite accurate and correlate well with blood levels. If salivary cortisol is high at 11 pm, it is indicative of Cushing syndrome.

Another useful method to determine the overproduction of cortisol by the body is to measure cortisol in a 24-hour urine sample. Your doctor may instruct you to collect urine for 24 hours and then the cortisol level is measured in the collected urine. Because it is the average cortisol level over a 24 h period, the measurement is not affected by stress or activity. If the urine cortisol level is high, it is suggestive of Cushing syndrome.

The third test is called low-dose DST or ‘low-dose dexamethasone suppression test’ (please see our separate blog on DST for an explanation of this test).  You will be asked to take 1 mg of dexamethasone (cortisol-like medicine) at 11 pm and get blood cortisol levels drawn the next morning around 8 am.  In a normal person, the blood cortisol level should be very low but in those with Cushing syndrome, the levels remain high. 

If you have classic symptoms and signs of Cushing syndrome, an abnormal 24 h urine cortisol level or two 11 pm salivary cortisol levels will confirm that you have Cushing syndrome. If 2 out of the 3 tests described above are abnormal, Cushing syndrome is also likely to present.

In mild cases of Cushing syndrome, cortisol levels may be only slightly abnormal or borderline high. In such cases, serial measurements are needed before a diagnosis can be made with confidence. 

Once Cushing syndrome is diagnosed and cortisol overproduction is established, blood ACTH level is ordered. If the blood ACTH level is low, it indicates that the excess cortisol is coming from the adrenal gland and a CT scan of the adrenal gland should be done next. If the ACTH level is normal or high, the excess cortisol is coming from the pituitary gland or other rare tumors and an MRI of the pituitary gland or/and CT scan of the chest/abdomen will be needed. A pituitary adenoma (a small benign tumor) may be visible on the MRI. On some occasions, more advanced testing is necessary to establish the cause of Cushing syndrome. These tests include nuclear scans such as an Octreotide scan and invasive tests such as pituitary sinus sampling – a procedure, in which cortisol level is measured in a blood sample from the pituitary gland. This sample is obtained through a catheter inserted into a vein in the groin and advanced under X-ray guidance to veins draining the blood from the pituitary gland. 


Treatment depends on the cause and may include surgery, radiation, or cortisol-reducing medications. If you are diagnosed to have a pituitary microadenoma causing ACTH-dependent Cushing syndrome, a referral to a tertiary care center with expertise in pituitary surgery is recommended. The surgical procedure is called transsphenoidal hypophysectomy or transsphenoidal pituitary resection. The surgeon approaches the pituitary gland using a tiny, specialized surgical instrument inserted into the nostril, alongside the nasal septum. This instrument then penetrates the sphenoid sinus (a hollow space on either side of the nasal cavity) to remove the tumor from the pituitary gland.

If you have an adrenal tumor, the tumor can be removed by a laparoscopic surgical procedure. Consult with a surgeon who is considered an expert in adrenal surgeries (usually an endocrine surgeon or some experienced general surgeons and urologists). Successful surgery can restore normal blood cortisol levels, although recovery may be slow, and follow-up with an experienced endocrinologist is recommended. Normalizing of blood cortisol levels will help reduce complications of untreated Cushing syndrome such as diabetes, osteoporosis, infections, heart attacks, and stroke. 

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