This article was last reviewed on
This article waslast modified on
7 January 2018.
What is it?

Cushing’s syndrome is a group of signs and symptoms caused by overexposure to too much of a hormone called cortisol. This hormone is produced in the body by the adrenal glands. There are two adrenal glands, one on top of each kidney. The control of production of cortisol from the adrenal glands comes from an area in the brain called the pituitary gland. This secretes a hormone called adrenocorticotrophic hormone (ACTH). This hormone stimulates the adrenal glands to produce cortisol. The pituitary gland itself and its production of ACTH are controlled in turn by the hypothalamus. The hypothalamus secretes a hormone called corticotrophin releasing hormone (CRH) which in turns stimulates the pituitary to secrete ACTH.

Cushing’s syndrome can therefore be caused by a variety of problems. The adrenal gland may itself be producing too much cortisol, or the gland could be being stimulated by excess ACTH or CRH production which in turn causes the adrenals to produce too much cortisol. This may be due to problems with the pituitary gland itself but may also be caused by tumours outside these areas producing large amounts of CRH or ACTH. Finally, Cushing’s syndrome can also be caused by a patient taking too much of a synthetic glucocorticoid (a steroid like cortisol e.g. prednisolone) for another clinical condition. This is the most common cause of Cushing’s syndrome.

As there are several possible causes of Cushing’s syndrome, for simplicity it is easier to divide them into those caused by excess ACTH production and those without.

Causes Related to Excess ACTH production

  • Cushing’s disease. A pituitary tumour that produces large amounts of adrenocorticotrophic hormone ACTH is known as Cushing’s disease. This is the most common cause of Cushing’s syndrome in this category (i.e. where there is excess ACTH production). In most cases the cause of the tumour cannot be found. In a small number of cases, the pituitary tumour that causes Cushing’s disease is part of an inherited condition known as multiple endocrine neoplasia type 1.
  • Ectopic ACTH. A tumour in the body not associated with the pituitary gland, which produces too much ACTH. This ACTH stimulates the adrenal glands to produce too much cortisol. This may be seen in lung cancer.
  • Ectopic CRH. A tumour in the body not associated with the hypothalamus that produces too much corticotrophin releasing hormone (CRH). This stimulates the pituitary to secrete large amounts of ACTH that in turn stimulates the adrenal glands to produce too much cortisol. This is commonly seen with small-cell carcinoma of the lung and bronchial carcinoid tumours but can occur with other tumours in the endocrine system.

Non excess ACTH related causes

  • Iatrogenic Cushing’s syndrome. Caused by taking synthetic glucocorticoids. These drugs, such as prednisolone and dexamethasone, act like cortisol.
  • Adrenal tumour. A tumour in the adrenal gland that produces too much cortisol. This is most often unilateral. These may be non-cancerous or cancerous.
  • Adrenal nodular hyperplasia. When groups of cells, or nodules, in the adrenal gland produce too much cortisol.
  • Genetic mutations. In some rare cases Cushing’s syndrome may develop because of gene mutations associated with other clinical conditions such as McCune-Albright syndrome.

Cushing’s syndrome can occur in anyone but is more common in certain groups of people, depending on the cause of the excess cortisol production. Pituitary adenomas and adrenal tumours for example are more common in women. In these cases it usually occurs between the ages of 25-40. It can however occasionally occur in children. Excess ACTH or CRH production due to lung cancers however would be expected in the elderly. Cushing’s syndrome is also more common in patients with diabetes, hypertension, obesity and osteoporosis. This is because Cushing’s syndrome can affect the body in such a way that these complications develop i.e. these diseases can be a result of the Cushing’s Syndrome.

 

Accordion Title
About Cushing Syndrome
  • Symptoms

    The signs and symptoms that occur with Cushing’s syndrome depend on a number of factors that include the cause of the Cushing’s syndrome, the level of cortisol or ACTHand the age and sex of the patient.

    They include obesity around the waist and also fat laid down across the shoulders and neck (sometimes known as a buffalo hump). In contrast arms and legs tend to be thin in relation to the rest of body. The face may be round and flushed (sometimes known as a moon face) and bruising is commonly present especially on the legs. Wounds may heal very slowly. There may be muscle weakness in the arms and legs, tiredness, ‘stretch’ marks around the stomach, hips and thighs. If ACTH levels are high there may also be pigmentation of the skin, particularly of scars and inside the mouth. There may also be psychological issues such as depression and difficulty concentrating. Other features include raised blood pressure (hypertension), too much blood sugar (diabetes) and fragile bones (osteoporosis). Women usually have menstrual irregularities. Men may suffer with impotence. In cases caused by a pituitary tumour there may also be headaches and visual disturbance.

     

  • Tests

    When a doctor suspects a patient may have Cushing’s syndrome they will do one of several possible screening tests. If the screening test indicates the patient may have Cushing’s syndrome, other tests will be carried out.

    Screening tests

    • A 24-hour urine test. A positive test is when the urine contains more cortisol than normal. The reliability of the test depends on the patient performing an accurate 24 hour urine collection.
    • An overnight dexamethasone test. Whilst at home, at 11pm the patient takes a 1mg dexamethasone tablet. Blood for cortisol measurement is taken the following morning at 9 am. In a normal person the dexamethasone (a synthetic cortisol-like drug) will cause the blood cortisol concentration to be below normal in the morning (cortisol concentration will be supressed). In Cushing’s disease this suppression is not seen and the cortisol levels are high.
    • Low dose Dexamethasone test. The overnight suppression test described above is a simplified version of the official low dose dexamethasone test. This version however may also be used especially if the results of the overnight dexamethasone test are inconclusive. In this test the patient has to take eight doses of 0.5 mg consecutively at 9 a.m., 3 p.m., 9 p.m. and 3 a.m. for a period of 48 hours before returning for a blood test to check cortisol levels. Again in a normal person the levels should be suppressed after taking the dexamethasone.
    • Dexamethasone suppressed corticotropin-releasing hormone (CRH) test: This test is a variation of the low-dose dexamethasone suppression test described above. 0.5mgs of dexamethasone is taken as mentioned but then IV CRH is given 2 hours after 48 hours. Serum cortisol is then measured 15 minutes after. Corticosteroid levels are measured 15 minutes after CRH administration. This is a very reliable test for Cushing’s Syndrome, but may only be available in specialist centres.
    • Cortisol measurements at 9am and midnight. Normally, cortisol levels within the bloodstream are higher in the morning (peak at 9am) and lower at midnight. In a patient with Cushing’s syndrome the midnight cortisol may also be high. This test is usually reserved for patients who are already in hospital as the blood needs to be taken from an indwelling cannula. ACTH may also be measured on the 9am blood sample. It may also be tested on a saliva sample which is more convenient than a blood sample.

    There are several reasons, such as drugs, anxiety and obesity, why the test may not be entirely reliable and the doctor may need to carry out further tests. If a screening test is positive further tests are carried out to determine the cause of Cushing’s syndrome.

    Further tests to determine the cause of Cushing’s Syndrome

    • ACTH. ACTH production is pulsatile with a peak at 8-9am. Blood samples for ACTH measurement must therefore be collected at this time of day. If the cortisol levels are high but ACTH levels are low Cushing’s syndrome is due to too much cortisol from an adrenal tumour or ingestion of synthetic steroids. This is because the body has a feedback mechanism whereby excess cortisol will switch off further production by lowering the production of ACTH. Therefore low levels indicate that the excess cortisol is not coming from overproduction of ACTH. A CT scan or MRI scan of the abdomen may follow to rule out any adrenal pathology causing the excess cortisol secretion. Conversely if the ACTH levels are high this usually means that there is excess ACTH production somewhere either by a pituitary tumour, excess CRH or a tumour elsewhere producing ACTH.
    • Extended dexamethasone test/High dose dexamethasone test. If ACTH levels are high it may be due to a pituitary tumour or a tumour elsewhere in the body. This test is used to distinguish excess ACTH production from either an ectopic tumour or from a pituitary tumour. Dexamethasone is given at different doses, four times a day, over four days. In a healthy person, dexamethasone will suppress ACTH secretion and hence cortisol secretion. Ectopic ACTH production will not normally suppress as much with high doses of dexamethasone whereas ACTH from a pituitary tumour usually does.
    • CRH test. CRH is given to test for pituitary ACTH deficiency and to differentiate between pituitary and ectopic source of ACTH in Cushings. This test may be performed at the time of inferior petrosal sinus sampling ( see below). A blood sample for ACTH and cortisol level is taken and then an injection of CRH is given 15 minutes later. Blood samples for ACTH and cortisol levels are taken again at 5, 15, 30, 45 and 60 minutes after the injection. In a normal person ACTH shows a maximum increase at 10-30 minutes and for cortisol a maximum increase at 30-60 minutes. Patients with pituitary Cushings show an increase in ACTH of at least 35-50% to CRH. This is much less than a normal person where the increase in ACTH is around 400%. Patients with Cushing’s syndrome, due to an adrenal tumour or ectopic ACTH production, show little or no increase in ACTH or cortisol.
    • Inferior petrosal sinus sampling (IPSS). This is an in depth procedure in which adrenocorticotropic hormone (ACTH) levels are determined in the veins that drain from the pituitary gland and are compared with the ACTH levels in the bloodstream. It is used to determine whether the raised ACTH levels causing Cushing’s Syndrome are due to an ectopic source or from a pituitary tumour. IPSS can also be used to establish on which side of the pituitary gland the tumour is located.

    Non-laboratory tests

    • Computed tomography (CT) scan. This is used to examine the pituitary, adrenal glands and other parts of the body for tumours.
    • Magnetic Resonance Imaging (MRI). This is used to examine the pituitary and adrenal glands for tumours.

     

  • Treatment

    The aim of treatment is to remove the cause of the excess cortisol production.  The type of treatment will depend on the cause.

    If the cause is due to too much synthetic glucocorticoid the patient’s doctor will try to reduce the dose of the steroid to reduce the symptoms of Cushing’s syndrome. It may not be possible to stop the symptoms completely. The patient must never stop taking the steroids abruptly and should only reduce the dose under the direction of their doctor.

    If the cause is due to an ACTH-producing tumour or ectopic ACTH production (see causes of Cushing syndrome, What is it) surgery, radiation, and in the latter case, chemotherapy may be carried out.

    In primary adrenal carcinoma, surgery is usually the only option available for treatment.

    If the cause is due to an adrenal tumour, or over-production of cortisol by one adrenal, then surgical removal of that adrenal will often bring the cortisol levels back to normal.  For a time, synthetic glucocorticoids may have to be taken since the activity of the other adrenal gland may have been suppressed by the excess cortisol.  It may be many months before the synthetic steroids can be stopped.  Again the patient should only change the dose or stop these steroids under the direction of their doctor.