The majority of patients with acromegaly have a pituitary macroadenoma, which frequently extends outside the sella and may result in compression of the optic apparatus and visual failure (5). Most tumors secrete GH alone, but up to a third result in hyperprolactinemia (6). This may result from tumoral cosecretion or stalk compression. GH-secreting adenomas occur either spontaneously or in the context of genetic conditions, such as multiple endocrine neoplasia (MEN)-1, McCune-Albright syndrome, and Carney complex syndrome. Once the diagnosis of acromegaly is established, surgery is the primary treatment of choice, resulting in a rapid reduction in circulating GH levels and reduction in the size of the abnormal pituitary gland. The majority of lesions are approached by the transsphenoidal route, but larger tumors extending above the sella may require transcranial operation (7). Microadenomas are frequently "cured," but this is seen in less than 50% of macroadenomas.
After pituitary surgery, both residual pituitary function and the GH secretory status should be evaluated. Basal endocrine testing for 9 am cortisol, thyroxine, TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone/estrogen, PRL, and serum and urinary osmolality should be performed before discharge. When there is doubt, assessment of ACTH reserve should be performed as outlined subsequently.
GH secretory status can be assessed using a five-point GH day curve (Appendix 1, see pp. 200-201). In acromegaly, GH secretion loses its normal pulsatile pattern, and values do not vary widely throughout the day. Serum insulin-like growth factor-I (IGF-I) is a marker of hepatic GH responsiveness and correlates well with GH levels (8), but age- and sex-normalized ranges are required. Recent evidence suggests that assessment as early as 1 wk postoperatively will allow for prediction of outcome. Because prolonged GH excess contributes to major morbidity and more than a doubling in cardiovascular and cerebrovascular mortality, efforts should be taken to ensure safe levels of GH in the circulation (9,10). In difficult cases, an oral glucose tolerance test may be necessary. Current evidence indicates that average serum GH concentrations <5 mU/L (2 ^g/L) reduce morbidity/mortality to that of a background population when associated with normalization of the serum total IGF-I concentration (11). A recent consensus statement defined cure as a nadir GH after an oral glucose load <1 ^g/L (approx 2 mU/L), provided the total IGF-I was within the age-matched normal reference range (12). However, many would use assessment of mean GH levels to <5 mU/L (2 ^g/L) as a more clearly established criterion. Most endocrine centers treat patients with acromegaly with the intention of achieving this level. After pituitary surgery, an early GH day curve combined with serum total IGF-I measurement will indicate whether surgery alone has been sufficient (13).
Current evidence suggests that in patients with acromegaly secondary to a GH-secreting microadenoma, surgery alone will result in cure in approx 70%-90% of patients. This figure falls when a macroadenoma (<50%) or a giant adenoma (<20%) is present. Those with the highest preoperative GH concentrations are least likely to be cured by surgery alone (13,14). In those with continuing GH excess, further treatment is indicated, and the majority of patients will undergo conventional fractionated three-field external beam irradiation. A second surgical procedure will result in safe GH levels in only 20% of patients (14).
Recognizing that radiotherapy does not result in an instant lowering of GH levels, medical treatment is commonly used, especially in the short-term. On average, 2 yr after external beam irradiation, GH levels have decreased by approx 50%, with a further fall resulting in 75% reduction at 5 yr (15). Newer stereotactic techniques, when used appropriately, may effect a more rapid reduction in GH levels. However, because the tumor in such cases is usually a macroadenoma, we would only use radiosurgery as "salvage therapy" in the face of poor control of tumor secretion or regrowth after conventional radiotherapy.
Additional available medical therapies include the use of dopamine agonists and somatostatin analogs (16). Bromocriptine will normalize GH levels in only 10% of patients, although this may rise to 30% with the newer agent cabergoline. Octreotide and lanreotide, particularly in their depot formulations, which last 46 wk, will normalize mean GH levels in 70%-80% of patients and are, therefore, highly effective, albeit expensive. The recently developed GH receptor antagonist, pegvisomant, may be used in patients resistant to these agents, when it eventually becomes available (17). Periodic assessment with IGF-I measurement and GH day curve testing should be performed at regular intervals to facilitate titration of doses and determine response to radiotherapy. After irradiation it is reasonable to assess GH status after appropriate discontinuation of medical therapies at 6-mo intervals for 2 yr and yearly thereafter.
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