Acromegaly

Acromegaly

What is acromegaly?
The name “Acromegaly” comes from the Greek words for “extremities” (acro) and “great” (megaly). Acromegaly is a hormonal disorder that results from too much Growth Hormone (GH) in the body. The pituitary, a small gland situated behind the bridge of your nose and at the base of the brain, makes GH. Acromegaly is caused by a benign (non-cancerous) tumour of the pituitary gland, which is called an adenoma and this causes the pituitary to produce too much GH.

Growth hormone-releasing hormone is made by the hypothalamus, a gland in the brain situated just above the pituitary, which stimulates the pituitary gland to produce GH. Secretion of GH by the pituitary into the bloodstream stimulates the liver to produce another hormone called Insulin-like Growth Factor 1 (IGF-1). IGF-1 is what actually causes tissue growth in the body. Growth hormone has effects on many different parts of the body; in adults it is important to maintain normal energy levels and to keep body tissues, such as muscle and bone, healthy. In children, of course, it is essential to reach normal growth.

Acromegaly usually develops in adults between the ages of 30 and 50, but symptoms can appear at any age. If acromegaly develops before you have stopped growing (which usually occurs between the ages of 15 to 17) it can cause gigantism, where people are very tall, because GH promotes growth of legs and arms. As the growth of bones stops after puberty, excessive GH in adults won’t result in increased height, but may cause various other changes outlined on the next page. Acromegaly is a rare condition with only around 4 - 6 new cases per million of the population being diagnosed each year. The diagnosis is often delayed as the symptoms develop gradually over time, and patients and families may not notice the changes. Patients may have had acromegaly for several years before the condition is recognised.

What are the symptoms of acromegaly?
Early symptoms may involve tiredness and sleep disturbance and swelling of the hands and feet. Patients may notice a change in ring or shoe size, and particularly the width of their feet. Gradually, bone changes alter the patient’s facial features with the brow and lower jaw protruding. The nasal bone enlarges and teeth may be spaced out. An overgrowth of bone and cartilage can lead to arthritis and when tissue thickens it may trap nerves, causing carpal tunnel syndrome which results in weakness, numbness or pain in the hands. Organs in the body, such as the heart may enlarge.

Other symptoms of acromegaly can include:
• Enlarged lips, nose and tongue
• Deepening of the voice due to enlarged vocal cords and sinuses ~
• Thicker, coarse, oily skin
• Joint aches
• Excessive sweating and skin odour
• Skin tags - tiny flesh-coloured finger-like projections on the skin
• Loss, or lack of libido
• Erectile dysfunction in men
• Abnormalities of the menstrual cycle and sometimes breast discharge in women
• Headaches
• Fatigue and weakness
• Impaired vision
• Sleep apnoea - breaks in breathing during sleep due to obstruction of the airway
• High blood pressure

How is acromegaly diagnosed?
If your doctor suspects acromegaly, the Growth Hormone (GH) level in your blood would be measured. However, a single blood test of an elevated GH level is not sufficient to diagnose acromegaly, as GH is secreted by the pituitary in spurts and results can vary widely from minute to minute.

A suppression test, or oral glucose tolerance test, is a more accurate way to measure GH. This involves drinking a glucose solution which in healthy people would lower GH levels, but in those with acromegaly this suppression of GH levels does not occur.

IGF-1 levels can also be used, as high levels are a sign of excess GH activity, which is the hallmark of acromegaly.

After acromegaly has been diagnosed by the above testing, a Magnetic Resonance Imaging (MRI) Scan of the pituitary is used to locate and detect the size of the tumour causing excessive GH production. Usually an area of pituitary abnormality is seen on the MRI scan but occasionally the tumour is too small to be seen. Very rarely, a tumour elsewhere in the body may produce GH releasing hormone which stimulates the pituitary to produce excessive GH. Such tumours will be identified with additional CT or MRI scans.

Further tests such as field of vision tests may be carried out to assess whether the tumour is causing any pressure on the optic nerves, as these nerves pass very close to the pituitary gland.

 Other blood tests may be taken to check if other pituitary hormones are affected such as cortisol, thyroid and sex hormones.

How is acromegaly treated?
Treatment options include surgery, medical therapy and radiotherapy. The goals of treatment are to: • Reduce excess GH to normal levels
• Relieve any pressure that the growing tumour may be exerting
• Preserve normal pituitary function, or to treat any hormone deficiencies
• Improve the symptoms of acromegaly

Studies show that untreated acromegalic patients are more likely to suffer from diabetes, high blood pressure and heart problems with a reduced life expectancy compared to the normal population. These can be improved after the successful treatment of acromegaly.

Acromegaly may be treated by surgery to the pituitary gland to remove or reduce the size of the tumour, by radiotherapy, by drug treatment, or a combination of these. Nowadays, for many patients the first treatment is surgery, although in some centres drug treatment to reduce the size of the tumour is given first. The aim of all treatments is to reduce growth hormone and IGF-1 levels to normal, in order to improve the specific symptoms of acromegaly in addition to general well-being.

Surgery
The operation is usually carried out by making a small cut in front of the upper teeth behind the upper lip, or through the nose. This is called Trans-sphenoidal Surgery. By going behind the nose like this, the surgeon can see your pituitary gland without having to operate on the main part of your head. In some centres an Endoscopic approach is used - fine tubes called endoscopes are pushed through the back of the nose, involving a small incision.

Most patients can be treated very successfully this way, although results are usually better if your tumour is small. The operation takes about an hour and a half. You will normally be in hospital for about five days. For the best results it is important to be referred to an experienced pituitary surgeon and your endocrinologist will be able to advise whom you should see.

See our booklet entitled Pituitary Surgery and Radiotherapy for further details about the operation. Surgery will normally lower your growth hormone levels considerably, but in some instances the acromegaly is not cured. In such cases, consideration will be given to treating you further with radiotherapy and/or drug therapy.

Radiotherapy
Radiotherapy (treatment with radiation) might be needed if your surgery has not been completely successful (not all the tumour could be removed) or if it was not possible for you to have an operation. The most common reason for incomplete tumour removal is proximity to the important blood vessel supplying the brain (internal carotid artery). In this situation, the surgeon may decide that it is safer to leave some of the tumour behind and rely on other ways of lowering GH. If you are given radiotherapy, it will be planned and carried out with extreme care. Using the images from your MRI or CT scans; the radiotherapy team will spend time planning exactly where the X-rays will be aimed.

You will attend the clinic on two or three occasions to have a special mask or fixation device made. This is a clear plastic mask or device which is used to hold your head still and ensure the radiation beams are correctly aligned. Treatment - very low doses of radiation - is usually given through three parts of the head - one on top of your scalp, and one area just beside each ear. The treatment itself usually comprises 5 - 6 weeks of daily treatment (Monday to Friday). It may take several months, or even years, after the treatment for the effects of radiotherapy to be complete. While you are waiting for this, you may be given drug treatment to improve control of GH levels.

Improvements in pituitary scanning and computerised control of radiotherapy mean that new forms of finely focused, high dose radiotherapy (stereotactic) are being developed. This treatment is not suitable for all pituitary tumours and its benefit is being evaluated. Stereotactic radiotherapy allows much higher doses of radiation to be given to a part, or occasionally the whole, of the tumour often in a single session. The larger dose of radiation means that your GH levels come under control much more quickly, maybe months rather than years. The Gamma Knife, the best-known form of stereotactic radiotherapy, is currently not widely available in the UK.

For more information about radiotherapy, see our booklet entitled Pituitary Surgery and Radiotherapy.

Drug Treatment
There are three types of drugs for treating acromegaly - each acts by different mechanisms: Somatostatin Analogues work on specialist markers (somatostatin receptors) to inhibit GH release from the tumour.
There are two somatostatin analogues available for the treatment of acromegaly:
Octreotide (brand name Sandostatin, manufactured by Novartis).
Lanreotide (brand name Somatuline, manufactured by Ipsen).
Octreolin This is an investigational new oral drug being developed for use in acromegaly.
Octreolin is an oral formulation of injectable Octreotide, a somatostatin analog with proven efficacy and safety that is commercially available only by injection.
Dopamine Agonists work on alternative markers (dopamine receptors) on the surface of the tumour to inhibit GH release from the tumour by a different mechanism.
Pegvisomant A new drug which works differently and blocks the action of GH and reduces IGF-1 levels.

Somatostatin Analogues
Somatostatin analogues require injections. Octreotide can be given once a month deep into muscle (intramuscularly) for the long-acting preparation (Sandostatin LAR, Novartis), or, occasionally, three times a day under the skin (subcutaneously). The short-acting preparation of octreotide is provided as ampoules or vials, which can be used for several doses. It is normally kept in the fridge, but must be removed and come naturally to room temperature before use. The long-acting preparation is usually given by a nurse at your GP surgery.

Lanreotide (Somatuline Autogel, Ipsen) is available as a once per month depot injection. A depot injection means it is a slow release medication injected.

Octreotide and Lanreotide help the symptoms of acromegaly by reducing growth hormone levels into the target range of less than 1.8/2 ug/l in more than half of patients (units of measure for growth hormone changed from mU/l to ug/l, therefore all values ug/l are approximately 1/3 of previous mU/l values). When you first start taking somatostatin analogues, it may give you stomach colic or diarrhoea, but these effects usually wear off within a few days. Some patients find that stomach problems improve if they do not inject for about two hours after eating. In the longer term both may cause gallstones, but these very seldom cause problems.

In general, the effectiveness and side-effects of long-acting somatostatin preparations are similar to the three times daily octreotide but you may prefer the convenience of only having to have an injection once a fortnight or once a month. The injection into muscle needs to be given by a nurse.

Dopamine agonists
There are several dopamine agonists available, all are taken by mouth but only two are widely used: Cabergoline (brand name Dostinex, manufactured by Pfizer)
Bromocriptine (brand name Parlodel, manufactured by Novartis)
Cabergoline, a newer long-acting dopamine agonist that causes fewer side-effects than bromocriptine, appears to be more effective in lowering GH and IGF-I levels, and needs to be taken only twice weekly. It is not licensed for the treatment of acromegaly but is an accepted and widely used treatment. Dopamine agonists used in very high doses to treat Parkinson’s disease have been shown to cause heart valve changes in some patients but studies in patients receiving cabergoline for acromegaly have been reassuring in this respect.

Therefore, patients using Cabergoline for pituitary conditions will need to have regular echocardiograms (heart scans). Your endocrinologist or GP will arrange this for you. Bromocriptine usually needs to be taken two or three times a day.

Unfortunately, although dopamine agonists are taken by mouth, they are often less effective than somatostatin analogues which have to be injected. They may cause you to be constipated, although this can be alleviated by increasing the fibre in your diet. At the beginning of treatment, you may also suffer nausea or dizziness when you first stand up. These effects also tend to wear off with time.

Pegvisomant
Pegvisomant (Somavert, Pfizer) is a completely different way of treating acromegaly. All current forms of treatment attempt to lower the amount of GH released by the pituitary gland. Pegvisomant is a blocker of the action of GH. It does not try to inhibit the release of GH from the pituitary into the blood but instead stops the GH leaving the blood to stick to cells throughout the body. This should block all the unwanted effects of GH and studies in patients with acromegaly suggest it is very effective. It is given as a daily subcutaneous (under the skin) injection. It is currently used for patients in whom the more traditional treatments have not been successful.

Effects of treatment
Once treatment is successful, you should notice that the soft tissue in your hands and feet decrease in size and patients often notice that their facial features gradually return towards normal. This may take some time, but do not despair - improvements will happen once treatment is successful.

If you were suffering from excess sweating this should decrease and if you had sugar diabetes, it should improve, or disappear altogether. Your headaches will usually improve and so will any visual disturbances that may have been present beforehand. If you snored, it should be improved. Some bone growth will usually decrease (such as the supra-orbital ridges) but main bone growth (for example: hands, feet and jaw) will remain the same.