Pituitary News, Issue 15 - Spring 2000.

What is Cushing's? The effects of Cushing's, treatment options, surgery and hormone replacement.

Professor Clara Lowy MD, FRCP
Guys, Kings and St Thomas School of Medicine, London

Cushing's syndrome

Harvey Cushing, an American neurosurgeon, was one of the first to describe the condition in 1932 in the Bulletin of the John Hopkins Hospital. Cushing's syndrome describes the condition resulting from excess exposure to steroid hormones. The commonest cause of Cushing's syndrome (apart from the use of synthetic steroids for other conditions) is Cushing's disease, a problem arising in the Pituitary gland.

So what is Cushing's disease?

This is caused by a tumour of the pituitary gland which overproduces a hormone ACTH, which in turn stimulates the Adrenal glands to overproduce the steroid Cortisol. Cushing's disease is commoner in women. It can affect all age groups, including children, but the peak incidence is middle age.

What is the effect of excess cortisol secretion on a patient?

Almost all patients gain weight due to an avid appetite. They are constantly hungry. The weight gain is not even, it tends to accumulate as fat on the trunk and face, giving the patient a portly, moon-faced shape. Less obvious is the simultaneous muscle loss, affecting mainly the shoulders, hips and thighs. This results in weakness and the patient often has difficulty getting up from a squatting position or from a low armchair or when stepping onto a bus. Sometimes a patient may fall and if there is no helping hand, the individual may not be able to get on their feet. The skin becomes thin and fragile, leading to cuts and bruising following trivial injuries. It can also become stretched, especially on the abdomen, resulting in red stretch marks, called striae. Also the bones may become thin (osteoporotic) making them fragile. Fractures of the ribs are common and often the patient is not aware of their occurrence. Cushing's patients can retain salt and water in their bodies leading to general swelling, often best seen as swelling around the ankles, and a rise in blood pressure. High blood cortisol levels can also affect brain function. Most patients experience sleep disturbance, waking in the early hours and having great difficulty in getting back to sleep. Some find they have to get up and busy themselves around the house. Many patients develop psychiatric symptoms of which depression is the commonest.

Cortisol increases the amount of sugar in the blood and this, combined with obesity, makes the body resistant to the effects of insulin, which can result in the development of diabetes mellitus. Cortisol also has an effect on the immune system rendering it less effective, and patients can become more prone to infections.

Usually the symptoms of Cushing's disease appear gradually over many months and sometimes several years. The severity of the condition also varies and the different features I have described are present in different degrees.

Once Cushing's is suspected, it is vital to confirm the diagnosis. This means referral to a hospital for blood tests and MRI scanning of the pituitary gland. Sometimes it is difficult to visualise a small Pituitary tumour and blood may need to be sampled for ACTH close to the pituitary gland: petrosal sinus sampling. This test requires special radiological expertise.

What are the treatment choices?

Once the diagnosis is confirmed, selective removal of the pituitary tumour, leaving the remainder of the gland intact, is the treatment of choice. This is not always possible and some of the healthy gland may also be sacrificed. If, as a result of the pituitary surgery, the healthy pituitary is damaged, then the patient may need to take a variety of hormone replacement treatments.

Sometimes it is not possible to remove all the cells making ACTH and better treatment is needed to cure the patient; if this is the case Radiotherapy of the pituitary may then be required. Radiotherapy may not be effective for some months and sometimes drugs such as ketoconazole or metyrapone can be given to control the disease until the radiotherapy takes effect.

Another solution is to remove both adrenal glands. However, whilst too much cortisol is harmful, none at all can be fatal and so, after Adrenalectomy, the patient has to take a replacement dose of cortisol (Hydrocortisone). Removal of the adrenal glands is usually performed either through small incisions at the back above the kidneys, or using a laparoscope ("keyhole" surgery). This has the advantages of a quicker recovery and smaller operation scars. While adrenalectomy results in a rapid resolution of all the Cushing's features, it leaves the cause of the disease (the pituitary) untreated. Sometimes this does not matter, but it may lead to the patient becoming more pigmented (looking very sun-tanned) and sometimes the pituitary tumour gets bigger. This can now be easily monitored with the MRI scanner. The pituitary tumour may have to be removed at a later date.

Following surgery, will you need hormone replacement?

The aim of pituitary surgery is to remove the small tumour making ACTH and leave behind the normal pituitary tissue. When this is successful there is often quite a prolonged period of time before the normal glandular tissue starts making ACTH. Until this activity returns the patients will not be making enough ACTH and hence enough cortisol and this hormone must be replaced. If the normal pituitary gland cannot be preserved during surgery, the patient may need replacement of cortisol, thyroid hormone, Sex hormones and/or Growth hormone.

Cortisol secretion varies with time of day, the highest levels occurring at 9am and the lowest levels at about midnight. Ideally, the tablets of hydrocortisone (replacement for cortisol) should be taken first thing in the morning and smaller doses at lunchtime and early evening. Hydrocortisone may irritate the stomach lining and if this occurs patients are advised to take tablets after meals. Not only does cortisol secretion vary with the time of day, it also rises during infections such as flu and under these circumstances the medication should be increased.

The pituitary also secretes TSH, which controls the Thyroid Gland. Replacement TSH is not available and Thyroxine, the product of the thyroid gland, is used instead. Thyroxine need only be taken once a day and the time of day makes no difference to its effect. The main action of thyroxine is to control the body's metabolic rate.

The sex hormones may also need to be replaced. For women, a combine 'Pill' or so-called hormone replacement therapy is appropriate. The time of day when medication is taken does not matter as long as the medication is no forgotten. For men, replacement is more complicated as there is no effective tablet. Treatment is either with injections of Testosterone (every 2-4 weeks), testosterone patches stuck on the skin or testosterone pellets which are inserted once every nine months or so under the abdominal skin. These treatments should prevent bone loss (Osteoporosis). They also help to restore sex drive.

More recently, growth hormone has become available for treatment of growth hormone deficient adults. This hormone has to be injected once a day, is very expensive and its ability to improve quality of life is still being assessed. It has been shown to reduce trunkal obesity, increase muscle bulk and strength and restore a sense of well being. Not all growth hormone deficient patients experience these benefits. In my experience, patients with Cushing's disease who have lost muscle bulk as a result of their disease, and who are unfortunate enough to lose their pituitary growth hormone gain most benefit from growth hormone replacement treatment.

Who should treat the Cushing's patient?

It has been shown for a variety of much commoner diseases, such as asthma or cancer of the breast, that once the diagnosis is entertained, units with a coherent team provide a better service that consultants working in isolation. For patients with pituitary tumours and who need surgical removal of the tumour, this team approach is most important. Neurosurgeons will then be dealing with sufficient numbers of patients to maintain their surgical skills. A recent review in the Lancet with respect to removal of pituitary tumours demonstrated that surgeons performing this procedure regularly obtain better results. The Pituitary Foundation may be able to advise patients if they are anxious about this. Indeed, this may be a particularly good time for the Foundation to raise the issue as to which specialists have the appropriate expertise for a particular health problem. The Minister of Health, Alan Milburn, has just appointed Professor Richards to oversee cancer services. Perhaps something might be done for patients with pituitary diseases.