Pituitary News, Issue 8 - Summer 1998.

Professor Paul Stewart of the Queen Elizabeth Hospital, Birmingham analyses some recent developments in the treatment of Acromegaly, in particalar the developments in medical therapy.

Acromegaly is an uncommon condition (prevalence 40-60 per million) resulting almost invariably from a Growth hormone (GH) - secreting Pituitary tumour. As with most endocrine conditions, a high index of suspicion is required by the doctor to ensure that the diagnosis is not missed and wherever possible diagnosed at an early stage.

Symptoms include coarsening of facial features, bone growth with enlargement of the hands and feet, joint pains, soft tissue swelling, high blood pressure, diabetes, muscle weakness and Carpal Tunnel Syndrome ("pins and needles" in the hands). Sleep apnoea and snoring, headaches and sweating are other common symptoms. In addition, patients may intially visit their doctor with symptoms associated with an ordinary pituitary tumour, for example failing vision and symptoms of hypopituitarism (lethargy, dizziness, cold intolerance, lack of periods, impotence). Blood tests show that acromegalic patients have elavated serum GH levels which fail to suppress following oral glucose load and IGF-1 hypersecretion; 30% of cases also have Hyperprolactinaemia. Finally it is now established that patients with acromegaly have an increased risk of earlier death (approximately twofold), predominantly due to excess deaths from cardiac, respiratory and malignant diseases.

The primary aims of treatment should be to remove symptoms, reduce tumour size and prevent regrowth of the tumour. Treatment options for acromegaly include surgical removal of the tumour, Radiotherapy, and reduction of GH levels by use of dopamine agonists (eg Bromocriptine) or Somatostatin analogues (Octreotide). Whether such treatment can truly 'cure' acromegaly is debatable and there is no real consensus as to what constitutes a cure. At present, therefore, most endocrinologists would aim to reduce GH to less than 5mU/l; at this level symptoms of the disease are usually controlled and life expectancy appears to be no different from the rest of the population.

So how often do we achieve a GH of less than 5mU/l in clinical practice? The policy of our own endocrine clinic has been to recommend surgery, which is followed by radiotherapy and/or medical therapy for patients with continuing symptoms and whose GH level remains too high. An audit of outcome of our patients treated with surgery and radiotherapy between 1985 and 1992 indicated that a GH value of <5mU/l was achieved in only 39% of cases, a result which is similar to that reported from other centres.

Bearing in mind that radiotherapy may take many years to exert its full effect, other treatments are needed if we are to achieve acceptable GH levels. Dopamine agonists such as bromocriptine, cabergoline and also quinagolide have been used and, whilst they do lower GH, particularly in patients with a tumour secreting both GH and Prolactin, they rarely result in GH falling to acceptable levels as defined above. Somatostatin is an endogenous hypothalamic peptide which inhibits GH release from the pituitary, but whose duration of action is very brief. Octreotide (Sandostatin, Novartis Pharmaceuticals) is a longer-acting synthetic somatostatin analogue which was first used in the mid 1980's. The drug is administered subcutaneously (ie by injection under the skin), three times daily in doses of 150-1500µg, and studies indicate that GH falls in over 90% of patients treated and to less than 5mU/l in approximately 40% of patients. IGF-1 is reduced to normal levels in about 50% of patients. The effect on tumour size is less convincing, with tumour size decreasing by more than 20% in only 44% of patients receiving octreotide subcutaneously.

For a given dose of octreotide, continuous release has been shown to be more effective than subcutaneous injections. This observation, along with the inconvenience of 3 daily injections, has led to the development of longer-acting preparations. Two such preparations have recently been launched, Sandostatin LAR (Novartis Pharmaceuticals) and Somatuline LA (Ipsen International). Both maintain sustained levels of the drug in the blood following a single Intramuscular injection, for 28 to 42 days in the case of Sandostatin LAR and for 10-14 days in the case of Somatuline LA. This contrasts to the peaks and troughs seen with the previously available subcutaneous injections.

Both preparations have been shown to be at least as effective as the subcutaneous preparations but, being a single intramuscular injection every 7-28 days, are much preferred by patients with acromegaly. GH reduces to less than 5mU/l in approximately 50-70% of patients, with IGF-1 reduced to normal in about 50% of cases. With a fall in GH, significant improvements have been seen in the disabling symptoms of acromegaly - sweating, headache, joint pains and tiredness. The preparations are safe, with no increase in GH levels seen in patients treated for up to 3 years (which are the longest studies reported to date). Gastrointestinal side effects (diarrohoea, constipation, abdominal colic) have been reported in 30-50% of cases but these are usually mild and transient, lasting for 1-3 days following the injection. Asymptomatic gallstones have been reported in 5-22% of cases and this may be less than the reported prevalence of 25-50% in patients receiving the previously available subcutaneous injections.

Somatostatin analogues are therefore an effective and well-tolerated treatment for acromegaly and the new preparations offer a major advance. The main situation where treatment with Sandostatin LAR or Somatuline LA is indicated is when the patient is not cured by pituitary surgery and/or radiotherapy. Ultimately cost-benefit analyses will have to be undertaken, but it is also possible that these well tolerated, highly effective preparations may be used as first line therapy for some acromegalics, for example patients who wish to retain fertility and those where the disorder is due to a small pituitary tumour (microadenoma).

The costs for these new long-acting drugs will be between £700 and £1000 per month, depending on the preparation used and the response of the patient. Initially, these intramuscular injections will have to be administered by a doctor or nurse. Clearly the introduction of such expensive treatment will require careful and ongoing negotiations between patients, hospital consultants and primary care physicians.

Acknowledgements: I wish to thank all the patients attending the endocrine/pituitary clinic at the University Hospital Birmingham NHS Trust for assistance with our studies analysing the effects of Sandostatin LAR and Somatuline LA. Without their help and other patients like them, these therapies would never become available for use.