Professor Stephen Shalet
University of Manchester

Generally, pituitary tumours are benign. They cause problems because:

• they arise in a finite space, leading to visual problems and headaches;
• they can secrete hormones in excess: Prolactin in patients with Prolactinoma, Growth hormone (GH) in Acromegaly and Adrenocorticotrophic Hormone (ACTH) in Cushing's disease;
• they can reduce the function of the pituitary (hypopituitarism).

Patients can suffer from one or a combination of these effects. Pituitary tumours which do not secrete hormones are described as non-functioning adenomas.

Prolactinoma

Dopamine agonist drugs are the dominant therapy for both macroadenomas (tumours larger than 1 cm) and microadenomas (smaller than 1 cm). The aim is to lower the prolactin levels to within the normal range, to reduce tumour size and to reverse hypopituitarism. Bromocriptine has been used for some time, but is now often replaced by cabergoline or quinagolide, because they have greater potency and fewer side-effects. One study with cabergoline showed a reduction in macroadenoma mass of 42% after 3 months of treatment, and an improvement of visual defects in 90% of patients.

Acromegaly

Treatment is evolving rapidly for this disease. Conventionally, surgery has been used for both microadenomas (with a high 'cure' rate of up to 80%) and macroadenomas (less successful at below 50%). If surgery is not completely successful, Radiotherapy may be used. This has a high (80%) success rate, but the effects can take up to 10 years to appear. The disease must be controlled by drugs in the meantime.

In some cases, especially when treating young people, radiotherapy may be avoided, to retain existing pituitary function and prevent infertility. Medical therapy is used instead. In addition, where the results of surgery are likely to be poor (e.g. for macroadenomas), patients may now receive medical therapy from the outset.

Drugs used in the treatment of acromegaly include the dopamine agonists (bromocriptine, cabergoline), Somatostatin analogues (now as long-acting depot preparations, lasting 10-30 days), and soon perhaps pegvisomant, a GH receptor antagonist which acts in tissues to prevent the effects of excessive GH. The efficacy of the somatostatin analogues is dependent on the post-operative GH level, and so drug therapy in this case is reliant on the success of surgery.

Cushing's disease

Pituitary surgery gives 75-80% cure rates at best. When surgery is not successful, it may be repeated, or a combination of radiotherapy and drugs used. In certain cases, a bilateral Adrenalectomy and pituitary radiotherapy may be chosen. Drugs such as metyrapone and ketaconazole may be used for pre-operative preparation, or post-operatively if the patient is uncured, either while waiting for radiotherapy to take effect, or alone to control the disease.

Radiation-induced hypopituitarism

This side-effect of radiotherapy is irreversible. It most commonly affects GH, but can cause pan-hypopituitarism (loss of all pituitary hormones). It is dose-dependent, and the level of deficiency is affected by how deficient the patient was before they received radiotherapy. It can take years to occur, so it is important to monitor patients regularly after treatment.

Non-functioning adenomas and hypopituitarism

Patients often have large tumours and experience mass lesion effects (headaches and visual problems). Surgery can lead to recovery of pituitary function (e.g. of TSH in 57% of cases, ACTH in 38%, FSH / LH in 32%, GH in 15%). Recovery is most likely in cases with small tumours and less severe hypopituitarism. GH deficiency is least likely to improve. Recovery begins immediately after surgery. The recurrence rate after surgery over 10 years is about 50%, while that after surgery and radiotherapy is about 5%, so radiotherapy will reduce the risk of recurrence in a significant number of the patients. However, selecting the cases for radiotherapy is not straightforward. Patients with residual tumour tissue after surgery have been found to be no more likely to show tumour recurrence than patients without clinical or radiological evidence of residual tumour, so this is not a good way of selecting whom to irradiate. Nonetheless, patients who are still hypopituitary after surgery can be offered radiotherapy without the penalty of losing further pituitary function.

Hormone replacement therapy

Hydrocortisone replacement therapy for ACTH deficiency is now better managed; doses have been reduced by about 30%, and administration now tends to be three times rather than twice per day.

GH replacement costs £3,000-£4,000 per patient per year. There is a high incidence of GH deficiency after radiotherapy, which is beginning to sway the balance towards using alternative strategies in cases where GH status is normal before therapy starts.

Conclusions

• New medical approaches are particularly exciting in the field of acromegaly.
• The optimisation of replacement therapy is underway.
• It is important to appreciate 'operator variability' among surgeons treating pituitary adenomas, and to try to remedy this.
• There is greater awareness of the 'destructiveness' of radiotherapy.
• More sophisticated neuroradiology gives us more useful strategies and alternatives.