Cushing's Syndrome & Cushing's Disease

Dr Caroline Jung (Endocrinologist) and Dr Warrick Inder (Endocrinologist)
Department of Endocrinology, St Vincent’s Hospital, Fitzroy, Melbourne


Cushing’s syndrome is a condition that results from long-term exposure to high levels of steroid hormones called glucocorticoids. Cushing’s syndrome can be caused by taking excessive amounts of glucocorticoid medications such as prednisolone or dexamethasone (exogenous Cushing’s syndrome) or from high levels of cortisol produced by the adrenal glands (endogenous Cushing’s syndrome). Although endogenous Cushing’s syndrome is rare, it is important to diagnose and treat this condition as it is associated with significant health problems and a shorter lifespan if left untreated. The main causes of Cushing’s syndrome are summarized in Table 1, the most common being Cushing’s disease, caused by a benign tumour (adenoma) in the pituitary gland that produces large amounts of a hormone called adrenocorticotropin (ACTH), which in turn increases cortisol production from the adrenal glands. This article will discuss the clinical features (symptoms and signs) and diagnosis of Cushing’s syndrome, and then focus on the treatment of Cushing’s disease in adults. The diagnosis and treatment of paediatric Cushing’s syndrome affecting children will not be covered here.

Table 1: Causes of endogenous Cushing’s syndrome


Frequency 1

ACTH-producing pituitary adenoma (Cushing’s Disease) 68%
Ectopic ACTH syndrome (bronchial, thymic, pancreatic, carcinoid tumours) 12%
Ectopic CRH syndrome <1%

ACTH-independent (adrenal causes of Cushing’s syndrome)
Adrenal adenoma 10%
Adrenal carcinoma 8%
Macronodular hyperplasia <1%
Micronodular hyperplasia 1%

Relative frequency refers to the percentage of individuals with Cushing’s syndrome who are diagnosed with the particular cause listed. For example, 68% of Cushing’s syndrome is caused by pituitary adenoma (Cushing’s Disease).

Normal cortisol production

The production and release of cortisol is controlled by a complex system involving hormones from the brain and pituitary gland (hypothalamic-pituitary-adrenal axis) (Figure 1). Corticotropin-releasing hormone (CRH) released from the hypothalamus causes the pituitary gland to secrete ACTH, which in turn results in the production of cortisol from the adrenal glands.

In healthy people, cortisol begins to rise between 3 and 4 am, reaches a peak between 7 and 9 am, and then falls for the rest of the day to the lowest levels when the person is unstressed and asleep at midnight. Cortisol controls its own production and release by switching off the hormones CRH and ACTH, a form of hormonal regulation known as “negative feedback”. ACTH and cortisol become elevated in response to stress, such as surgery, trauma, infection or other medical illnesses. Cortisol has many important functions which are essential for life, including maintenance of blood pressure and metabolism of carbohydrates, lipids and protein. However, abnormally high levels of cortisol have well-known negative effects on the body, such as weight gain, diabetes and high blood pressure.

Figure 1: Hypothalamic-pituitary-adrenal axis 


Figure 1

Jung Caroline/Inder Warrick J. Management of adrenal insufficiency during the stress of medical illness and surgery. MJA 2008; 188 (7): 409-413. ©Copyright 2008. The Medical Journal of Australia - reproduced with permission

Clinical features of Cushing’s syndrome

The symptoms and signs of Cushing syndrome are variable and no single pattern is seen in all patients. A common feature is weight gain, with increased fat accumulation around the chest, abdomen and face (“moon face”), while increased fat deposition between the shoulder blades (“buffalo hump”) and above the collarbones occurs less commonly. Low sex drive, raised blood sugar levels, elevated blood pressure, lethargy and depression are common clinical features in people with Cushing’s syndrome, while excessive hair growth and irregular periods may occur in women. However, obesity, diabetes and high blood pressure are also common in the general population, and they do not help to discriminate patients with Cushing’s syndrome from those without the disorder. Clinical features which are more specific for Cushing’s syndrome include muscle wasting and weakness, easy bruising, wide purple stretch marks and thin skin. However, these changes are not found in all patients with Cushing’s syndrome. The presence of unexplained osteoporosis or fracture in young people also may indicate Cushing’s syndrome.


1) Who should be tested?

The decision to test for Cushing’s should be made after a thorough clinical assessment, including a medication history to exclude people taking steroid medications. Testing for Cushing’s syndrome is recommended in patients with multiple and progressive features, particularly those that are more strongly suggestive, such as muscle weakness, easy bruising, wide purple stretch marks, thin skin, or osteoporosis in young people.

2) What are initial tests for Cushing’s syndrome?

The best screening tests for Cushing’s syndrome are the overnight (1mg) dexamethasone suppression test and midnight salivary cortisol. The use of 24-hour urinary free cortisol is less useful as a screening test because mild cases of Cushing’s syndrome may have normal levels, and it is a less convenient test for the patient.

The overnight dexamethasone suppression test involves a blood test between 8 and 9 am after taking 1 mg of dexamethasone the night before between 11 pm and midnight. In normal people, dexamethasone results in low cortisol levels on the following morning. In Cushing’s syndrome, cortisol does not properly suppress to these low levels. This test is not recommended for patients taking medications that alter the breakdown of dexamethasone in the body (for example, some epilepsy medications) or medications containing oestrogen (such as the oral contraceptive pill or hormone therapy). Some forms of illness or stress may also result in a higher than normal cortisol level after dexamethasone, but a low cortisol level of less than 50 nmol/L is very reassuring that the person is unlikely to have Cushing’s syndrome. Midnight salivary cortisol is measured on a saliva sample collected at home and the specimen is sent to the laboratory the following day. This test may be falsely high in shift workers who do not usually sleep at night, but is the screening test of choice in anyone on potentially interfering medications as outlined above.

General Practitioners or other specialist doctors may perform the initial testing for Cushing’s syndrome. If the screening test results are normal, assuming that there is no reason to doubt the results, then the patient is unlikely to have Cushing’s syndrome. Thus, the patient can be reassured and no further testing needs to be done, unless symptoms progress or new features develop over time.

3) Who should be referred to an endocrinologist?

The following groups of patients should be referred to an endocrinologist:

  • Individuals with an abnormal screening test result as described above
  • Individuals with normal screening test results but who have clinical features strongly suggestive of Cushing’s syndrome or suspected cyclical Cushing’s syndrome where the high cortisol levels may come and go.

In these situations, further evaluation by an endocrinologist will ensure that the diagnosis of Cushing’s syndrome is confirmed or excluded and that the possibility of a falsely abnormal or falsely normal result will be considered.

Further tests performed by an endocrinologist to confirm the diagnosis of Cushing’s syndrome may include the following:

  • 24-hour urinary free cortisol
  • Repeat salivary cortisol measurements over several nights
  • Other forms of dexamethasone suppression testing with or without CRH injection.

24-hour urinary free cortisol is the amount of cortisol that is passed by the kidneys into the urine per day. In patients with Cushing’s syndrome, 24-hr urinary cortisol levels are usually elevated, but may be normal in mild cases. It is important to follow the instructions carefully and collect all the urine passed in one 24-hr period into the bottle provided. Over- or under-collection may falsely elevate or lower urinary free cortisol results. This test is performed at least twice to minimize errors in the urine collection and test results.

4) What happens once the diagnosis of Cushing’s syndrome is confirmed?

Once the diagnosis of Cushing’s syndrome is confirmed, further tests will be performed to determine the cause. It is usually straightforward to separate adrenal Cushing’s (Table 1) from other causes by the finding of low ACTH levels in the blood. In patients with normal or elevated ACTH levels, the most common cause is an ACTH-producing pituitary tumour (Cushing’s disease). Less often, a tumour from another part of the body may produce excessive ACTH (ectopic ACTH syndrome) (Table 1). 

Some of the tests used to distinguish between these two causes may include:

  1. High-dose (oral or intravenous) dexamethasone suppression tests
  2. CRH stimulation test
  3. Imaging such as MRI scan of the pituitary gland, CT scan of chest and abdomen
  4. Bilateral inferior petrosal sinus sampling

The interpretation of laboratory tests used to distinguish between Cushing’s disease and ectopic ACTH syndrome is complex and these tests should only be done in centres with expertise in the diagnosis and management of Cushing’s syndrome.

Bilateral inferior petrosal sinus sampling may be required in some patients to confirm that the problem is coming from the pituitary gland, which is the most common site. This test is usually performed by a specially trained radiologist. Catheters (long hollow tubes) are placed in the femoral vein in the groin on each side, and moved up towards the head until positioned next to the pituitary gland. Several blood samples are taken to determine whether the high ACTH levels are coming from the pituitary gland.

Treatment of Cushing’s syndrome

First-line treatment: surgery

The best treatment for Cushing’s disease is surgical removal of the pituitary tumour, performed by an experienced neurosurgeon. Most pituitary tumours can be removed by an approach through the nose. Surgery is performed under a general anaesthetic and patients usually stay in hospital for about 5-6 days. Patients with Cushing's disease usually have small tumours less than 1 cm in diameter (microadenomas) and are surgically cured about 70-90% of the time. In patients with larger tumours, cure rates are lower (<65% in most centres). It has been shown that the success of surgery is dependent on the amount of experience the surgeon has at performing pituitary operations. Therefore, patients with Cushing’s disease should be referred to a neurosurgeon with a special interest in pituitary surgery to achieve the best rate of cure and fewer complications.

After pituitary surgery, blood and urine cortisol levels are measured to provide information on the likelihood of a cure. If cortisol levels are low or undetectable after surgery, it is likely that the entire tumour has been removed and the chance of a long-term cure is high. Cortisol levels above the normal range indicate persistent tumour. If the cortisol levels are normal, patients are watched carefully without further treatment, because these people have a higher rate of the problem coming back compared to those whose cortisol levels are low after the operation.

After a successful pituitary surgery where the cortisol levels are low, patients require small doses of replacement glucocorticoid medication (such as hydrocortisone 30-40 mg daily initially, divided into a morning and afternoon dose) until the normal pituitary and adrenal glands recover. It is common for people “cured” of their Cushing’s syndrome to feel worse for some weeks or months after the surgery, as the body gets used to having normal or low cortisol levels. Symptoms such as headache, fatigue and generalised aches and pains occur frequently. These can be relieved using higher doses of hydrocortisone, but ideally, a balance must be made between symptom relief and recovery from the Cushing’s. The hydrocortisone is gradually reduced as tolerated, starting with the afternoon dose. This process may take months or even years after surgery. While taking hydrocortisone, increased doses are required during times of stress (e.g., infection or surgery).

Patients with adrenal Cushing’s are treated with surgical removal of the adrenal tumour where possible. In the rare cases where both adrenal glands are involved, both should be removed. Most adrenal tumours are benign, but if the adrenal tumour is cancerous, the usual treatment involves the use of a medication called mitotane after surgery. Unfortunately, if an adrenal cancer has spread to other sites, the outlook is poor.

In cases of ectopic ACTH secretion, every effort is made to locate the source of the hormone in other body sites. Where possible, an operation is recommended to remove the source. Where the source is not found or is not operable, medical treatments or removal of both adrenal glands may be indicated.

Second-line treatment options

In patients with persistent or recurrent Cushing’s disease, treatment options include a repeat pituitary operation, radiotherapy, surgical removal of both adrenal glands (bilateral adrenalectomy), or medications.

  1. Radiotherapy

    Pituitary radiotherapy is curative in 50-100% of patients with Cushing’s disease. However, it usually takes 1-3 years for cortisol levels to normalize and treatment with medication may be required to control the high cortisol levels until the radiotherapy has its full effect.

  2. Bilateral adrenalectomy

    Removal of both adrenal glands can be performed by key-hole surgery in most patients. This provides immediate control of the high cortisol levels and achieves nearly 100% cure rate. Where the patient has had a pituitary tumour causing the Cushing’s syndrome, pituitary radiotherapy should be given first to prevent this tumour from enlarging. The main disadvantage is that replacement steroid medication is needed for life.

  3. Medical treatment

    Medications which decrease the production of adrenal steroid hormones include ketoconazole, metyrapone, and mitotane. These medications may be used before pituitary surgery, before bilateral adrenalectomy, or after radiotherapy while waiting for cortisol levels to normalize. Sometimes a synthetic glucocorticoid such as low dose dexamethasone is used in combination to prevent symptoms of cortisol deficiency. Newer medical treatments are also being developed and are undergoing clinical trials.


  1. Approximately 70% of Cushing’s syndrome is caused by a pituitary tumour producing excess amounts of ACTH (Cushing’s disease).
  2. The health problems associated with Cushing’s syndrome usually get worse with time, and therefore, prompt diagnosis and treatment are important.
  3. The clinical features which best discriminate Cushing’s syndrome from those without this disorder include muscle weakness, easy bruising, thin skin and wide purple stretch marks. The presence of unexplained osteoporosis or fracture in young people also warrants further investigation.
  4. In patients with suspected Cushing’s syndrome, either an overnight (1mg) dexamethasone suppression test or midnight salivary cortisol may be used as a screening test. These tests are simple to perform, but it is important to follow instructions carefully for each test to ensure that the results can be interpreted accurately.
  5. Further investigations are required to confirm the diagnosis of Cushing’s syndrome and then determine the cause (pituitary, ectopic or adrenal).
  6. The optimal treatment for Cushing’s disease is pituitary surgery performed by an experienced neurosurgeon. Adrenal and ectopic ACTH secreting tumours may also be suitable for surgical treatment.
  7. After successful surgery, patients require glucocorticoid medication until the normal pituitary and adrenal glands recover.
  8. In patients who are not cured by surgery, treatment options include radiotherapy, bilateral adrenalectomy, or medications. The benefits and disadvantages of these treatment options may differ between individual patients.
  9. Long-term follow-up is required to monitor for side effects of treatment and for the recurrence of Cushing’s syndrome.