Professor Michael Besser
St Bartholomews Hospital, London

The Hypothalamus translates electrical impulses in the brain into chemical signals. These stimulate the pituitary to secrete hormones into the blood, including adrenocorticotrophin (ACTH). ACTH acts upon the adrenals, stimulating them to produce corticosteroids, including glucocorticoids like Cortisol. Cortisol circulates around the body, and affects various organs. It normally reduces the amount of ACTH produced by the pituitary, and so regulates its own production by reducing ACTH's stimulation of the adrenals.

Problems at the pituitary or adrenal level can cause Cushing's syndrome, where the level of cortisol is raised. As cortisol has many effects, including metabolic actions and effects on the brain, these are directly altered in Cushing's. Patients also suffer effects that are indirectly related to increased cortisol, such as depression associated with changing body image, and these in turn can affect other people's attitudes to them, both conscious and subconscious.

Cushing's can be defined as the signs and symptoms associated with prolonged and inappropriate elevation of circulating free glucocorticoids. It is important that the elevation is prolonged - short-term elevations do not cause Cushing's - and it is important that the free level of hormone is measured - hormone bound to protein in the blood is inactive and does not count.

Features of Cushing's syndrome

Cushing's is six times more common in women. Patients tend to have central obesity (increase in trunk size not limbs), and protein wasting, which leads to thin arms and legs (due to muscle loss) and thin skin. Reduced skin thickness also results in a plethoric (purple) face, as blood is more visible through the skin, and purple striae (stretchmarks). Bruising occurs more easily. Fractures may result from thin bones/Osteoporosis. Cortisol's anti-insulin activity may lead to diabetes. Patients may also suffer from hypertension (high blood pressure), or depression/insomnia (a form of agitated depression). Effects on Sex hormones can cause hirsutism, loss of periods, acne, impotence and decreased libido. Susceptibility to infection may increase as cortisol suppresses the clinical features of infection. Growth may be stunted in children.

It is a complex disease which makes it difficult to manage. There are lots of exceptions to the rules.

Causes

True Cushing's syndrome can be:

1. ACTH-dependent -
   • Either a disorder of the pituitary where too much ACTH is produced (Cushing's disease)
   • Or 'ectopic', the excess ACTH coming from a non-Pituitary tumour, often in the lung. Large tumours can be easy to spot but are often rapidly fatal, while small tumours (about 2-3 mm) are difficult to find, and patients may have a long history.
2. Non-ACTH-dependent -
   • Adrenal tumours; most are benign.

In addition, there are doctor-induced Cushing's ('iatrogenic', e.g. caused by medication), and pseudo-Cushing's syndrome, which may be (a) caused by depression, and can be treated using anti-depressants alone (difficult to distinguish from a true Cushing's patient with depression) or (b) caused by alcohol, which can give a red face, fat belly, thin arms and legs, but the cortisol is only elevated while the patient is actively drinking too much alcohol.

Therapies for pituitary disease

Transsphenoidal surgery

The normal pituitary is about 9 mm in diameter and lies under the brain. Tumour size and location mean that the easiest approach is transsphenoidal (i.e. through the nose). This is the usual treatment, and has a 'cure' rate of 50-80% (the patients within this range show some disease recurrence). Successful surgery leads to cortisol's rapid disappearance from the blood.

Radiotherapy

This is used when surgery is unsuccessful.

Medical therapies

Drugs such as metyrapone, ketoconazole and o,p'DDD are used to control cortisol levels, particularly before surgery.

Bilateral Adrenalectomy and radiotherapy

If cortisol levels cannot be controlled using the above methods, the adrenals are removed and radiotherapy used. This was the method in general use before transsphenoidal surgery became an option.

Ideal management of Cushing's

1. Cushing's disease (i.e. pituitary cause) - as described above.
2. Ectopic ACTH syndrome - the tumour must be located and removed, wherever it is in the body; this can be very difficult.
3. Alcohol-induced syndrome - abstention from alcohol.
4. Depression-induced syndrome - treat the primary cause, the depression.
5. Adrenal tumours - surgical removal.

If these methods are incompletely successful, radiotherapy and/or chemotherapy can be used with intermediate medical therapy to control the disease.