Dr Jonathan Newell-Price
Northern General Hospital, Sheffield

Cushing's syndrome is caused by there being too much of the hormone Cortisol in the bloodstream, tissues and organs of the body over a long period of time (months to years). Cortisol comes from the Adrenal glands. These glands sit on top of the kidneys. The disease was named after Harvey Cushing - an eminent American neurosurgeon who described the first patients with this condition in 1912 and 1932.

The Pituitary gland, which is located underneath the brain, secretes the hormone adrenocorticotrophin, otherwise known as ACTH. This hormone passes in the blood stream to the adrenal gland and causes the gland to make cortisol. An area of the brain known as the Hypothalamus controls the pituitary. Normally the levels of ACTH and cortisol are high in the morning and low at night. In Cushing's the amount of cortisol is high most of the time.

Cushing's is rare. Of the various causes of Cushing's the most frequent one is a small (5 mm) tumour of the pituitary gland producing ACTH and causing the adrenals to make too much cortisol. Occasionally, ACTH can come from other parts of the body (ectopic ACTH). This is usually from a very small tumour, which can make it difficult to find the cause of Cushing's. The other main cause is an adrenal tumour making cortisol independently of ACTH. This is usually easier to diagnose, as the levels of ACTH in the blood are low.

Cushing's is not usually hereditary, although there are very rare conditions in which Cushing's can occasionally be in more than one family member. A patient with Cushing's may have children with other conditions such as diabetes, but the risk of this is the same as for parents who have not had Cushing's.

Surgery to the pituitary gland remains the first line treatment, usually following several weeks of treatment with tablet medication to lower the cortisol levels. This has the potential to allow cure of Cushing's, but to leave the rest of the pituitary gland working normally. Cure is achieved in approximately 55-65% of patients undergoing pituitary surgery. Of those not cured, half will still have an improvement in their condition with lower levels of cortisol. Some people need more than one operation.

If the cortisol levels in the blood immediately after successful surgery are persistently very low, experience in large numbers of patients shows that on long-term follow-up (more than 15 years) the Cushing's will not come back. However, the way in which this blood test is done is of vital importance if it is to be used to predict those people with Cushing's that are cured.

If the Cushing's is not cured by pituitary surgery and the cortisol levels remain high, then treatment with medication such as metyrapone and ketoconazole may be needed. Radiotherapy lowers the production of ACTH from the pituitary gland and this lowers the drive to the adrenal glands, which then make less cortisol. The usual form of radiotherapy can take months to years to take effect and tablet medication can be needed for this time. Careful monitoring with blood tests at regular intervals is required to keep a check on the level of cortisol and other hormones that come from the pituitary gland. Radiotherapy given in this way is a very safe, long-established and effective form of treatment.

There are other forms of radiotherapy, but these are less widely available and have not been used for nearly as many years. In some circumstances highly focussed radiotherapy may be appropriate and can, in some circumstances, be used in people who have had the conventional type of radiotherapy.

Surgery to completely remove the adrenal glands will cure Cushing's. However, this means that life-long treatment with Hydrocortisone (cortisol) tablets and fludrocortisone tablets will be needed. It is essential that all of both the adrenal glands are removed; otherwise the Cushing's may come back. Nowadays, this operation is best done by a specialist endocrine surgeon experienced in laparoscopic (keyhole) surgery, with joint management with an Endocrinologist. Surgery to the adrenal glands is particularly advised if it is difficult to control the Cushing's. Sometimes, even after pituitary surgery, the adrenal glands start to make cortisol by themselves (nodular hyperplasia) and adrenal surgery may be needed for this.

Before or after removal of both the adrenal glands radiotherapy to the pituitary is often needed.