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Given the chronic nature and associated significant increased morbidity and mortality of acromegaly, treatment is required for almost all patients. Three modalities of treatment are available: surgery, pituitary irradiation and medical therapy. All of these have advantages and disadvantages and more than one modality is frequently needed, often all three. The decision as to whether to treat and the modality employed must be based on a number of factors, including patient age and general health, wish for fertility, severity of disease and any associated complications, and the risk/benefit ratio of the proposed treatment modality. The goals of treatment are summarised in Table 4.
Table 4. Acromegaly- aims of treatment
- Removal of the pituitary tumour and resolution of mass effects
- Relief of the symptoms and signs of acromegaly
- Restoration of normal rates of secretion of growth hormone and IGF-I
- Maintenance of normal anterior pituitary function
- Prevention of recurrence
- Assessment and treatment of chronic complications
Whilst the general principles of these aims are accepted by all endocrinologists, there remains considerable controversy as to the degree of growth hormone reduction that should be the target and what level should be regarded as normal. The use of sensitive growth hormone assays has demonstrated that abnormal patterns of growth hormone secretion can remain despite reduction in mean circulating concentrations to extremely low levels, and thus complete restoration to normality is often not achieved. Early epidemiological reviews, particularly those documenting the results of surgery, tended to regard a mean level of less than 5 ng/ml as being satisfactory. It has become clear in recent years that the excess mortality associated with acromegaly can be significantly reduced and indeed restored to that of the normal population by aggressive treatment and reduction of serum growth hormone concentrations to a mean level of less than 2 ng/ml and/or a serum IGF-I within the aged-matched reference range. Thus, rather than using the word cure, it is may be more appropriate to consider an average growth hormone concentration of ? 2 ng/ml as representing a "safe" level. An alternative target suggested at a consensus conference is a nadir level of less than 0.4 ng/ml after a standard 75g glucose tolerance test 42 (Figure 2).
Surgery for Acromegaly Transsphenoidal surgery is the initial treatment of choice for most patients. Originally performed by Harvey Cushing in 1910, the lack of adequate visualisation prevented its reintroduction for routine use until the mid-1970's. With modern equipment and in experienced hands, it is a safe procedure with a low complication rate and mortality of less than 0.5%. The most commonly used approach is with the patient in a semi-reclining position via a mid-line nasal route. Using a sub-labial or direct nasal approach, the mucosa is cleaved off the nasal septum providing access to the sphenoid sinus and subsequent removal of the fossa floor. A less satisfactory alternative approach is via the ethmoidal sinus. Pituitary adenomas are usually soft and easily removed with curettes although firmer and larger tumours may require piecemeal removal. Using this technique, even tumours with a significant suprasellar extension can be removed via the transsphenoidal route, although massive tumours may require a craniotomy. Such transcranial surgery is however associated with increased morbidity and mortality. More recent surgical techniques include the use of intra-operative MRI43 and intra-operative growth hormone measurement44. The development of endoscopic transsphenoidal surgery has been reported to offer several advantages over the conventional technique, although is used by only a few surgeons. These include superior tumour clearance, especially suprasellar extension, less surgical morbidity, fewer complications, and reduced post-operative discomfort 45.
The success rate of transsphenoidal surgery depends on several factors: (i) the size of the tumour, (ii) pre-operative growth hormone values and (iii) the skill and experience of the surgeon46;47. Although different series have often used different criteria to determine success rates, in experienced hands post-operative mean growth hormone levels of less than 2 ng/ml should be achieved in 70%-90% of microadenomas and 30%-50% of macroadenomas48,49. Pre-treatment of patients with somatostatin analogues before transsphenoidal surgery results in significant shrinkage (approximately 50%) of the adenoma and may improve the subsequent surgical cure rates50;51. Complications of transsphenoidal surgery include diabetes insipidus; this is usually transient but may be permanent in approximately 5% of cases depending on the criteria for its diagnosis. A serum osmolality of greater than 295 mosmols/l with a simultaneous urine osmolality of less than 150 mosm/l is confirmatory. It responds well to desmopressin (DDAVP, subcutaneous, oral or intranasal). Other complications include CSF rhinorrhoea and subsequent risk of meningitis, although this can be minimised by the use of prophylactic antibiotics. The syndrome of inappropriate ADH (SIADH) may occur around one week post-operatively and needs to be considered in the context of decreased urine output ? such a clinical scenario must be distinguished from hypovolaemia due to insufficient fluids; increasing intravenous fluids for the latter erroneous diagnosis will obviously dramatically worsen SIADH which almost always spontaneously resolves after a short period of fluid restriction.
The major long-term complication associated with transsphenoidal surgery is worsening of anterior pituitary function and hypopituitarism. In a series of 100 patients with acromegaly operated on at St Bartholomew's Hospital, UK, new hypopituitarism occurred in 21% of patients following surgery, but with 35% having hypopituitarism pre-operatively52.