Acromegaly

Symptoms develop insidiously, taking years to decades to become apparent, with a mean duration of symptom onset to diagnosis of 12 years.
Macroadenomas are detected in approximately 80% of patients with acromegaly, a reflection of the delay in diagnosis. Therefore, tumour debulking and appropriate adjuvant therapy may reverse, reduce, or even prevent mass effects caused by tumour growth. The mortality rate of patients with acromegaly is 2 to 4 times higher than the expected rate, primarily attributable to cardiovascular disease. Treatment that normalizes serum insulin growth factor (IGF-I) levels abolishes this risk.

Diagnosis
1. As Growth Hormone is secreted in pulsatile manner and there is a wide range secreted in a day, random measurement may not provide the abnormal picture. As basal levels after glucose suppression are invariably high in acromegaly, oral glucose suppression test (OGTT) is used to diagnose acromegaly.

75 gm of oral glucose is given in 100 ml of water and serum GH levels are measured at 0, 30, 60 and 90 minutes respectively. If GH levels do not fall below 1 ng/ml, diagnosis of acromegaly is confirmed.

2. Serum IGF I levels reflect the GH levels in the blood in last 24 hours and should be checked pretreatment to act as baseline. A strong correlation exists between serum IGF-1 levels and 24-hour mean GH levels after an OGTT.

A. Surgery
Transsphenoidal route is the approach for tumour resection in most cases.
Remission is defined by normal age-adjusted serum IGF I and glucose suppressed levels less than 1 ng/ml with older GH assays and less than 0.4 ng/L with newer, more sensitive GH assays. 65%-70% patients achieve remission following surgery. Patients in remission following complete resection don’t need further treatment and should be kept on observation and follow up evaluations.

For patients who do not attain normal serum IGF I and glucose suppressed GH levels after surgery, subsequent treatment in the form of medical therapy or radiation therapy is required. Patients achieving normal serum GH levels after glucose suppression but not normal IGF I levels may be observed as the evidence for treatment is not clear. However, patients who have glucose suppressed GH levels greater than 1 ng/ml but normal serum IGF I levels, need medical treatment. Medical therapy is very expensive and many patients may not afford this (especially life long treatment). Radiotherapy takes years in bringing GH levels and IGF I levels to normal and medical therapy should be offered awaiting the beneficial effects of irradiation.

B. Medical therapy
1) First line for patients considered high risk for anaesthesia complications due to airway difficulties or having systemic manifestations of acromegaly as severe hypertension, uncontrolled diabetes or cardiomyopathy. Some of the patients become suitable for surgery after medical treatment and risks of surgery and anaesthesia are potentially reduced.

2) For patients not achieving remission following surgery and/or radiotherapy

a) Dopamine agonists: Cabergoline and bromocriptine: these were the only choices in the treatment prior to somatostatin analogs. These are less efficient as compared to somatostatin analogs. However, these should be considered for patients not affording or not responsive to somatostatin analogs.

b) Somatostatin analogs: Somatostatin analogs work through several mechanisms to reduce GH excess: They suppress growth hormone-releasing hormone action, suppress GH secretion from the adenoma, decrease GH binding to hepatocyte GH receptors, inhibit hepatic IGF-1 synthesis, and prevent further growth of the pituitary adenoma. The fall in GH level is inversely proportional to initial levels. A complete normalisation occurs only in 60%-70% of patients. Once normalised, GH should be measured annually. The treatment is more effective in patients who have undergone surgery & radiotherapy as opposed to de novo treatment.

Reduction in tumour size has been found to occur in 30%-40% of patients.

c) GH receptor antagonist: Pegvisomant, a GH receptor antagonist, acts on GH receptors to block GH action. Unlike the other types of therapy for acromegaly, the action of this drug is not to reduce circulating GH levels but to normalize IGF-1 levels by blocking GH receptor signalling events. Pe gvisomant has shown strong efficacy, with over 90% of patients achieving normalization of IGF-1 levels. There is significant improvement in the signs and symptoms of acromegaly as well as correction of metabolic defects such as insulin resistance, associated with this good biochemical control. The drug is administered once daily by subcutaneous injection in range of 10-40 mg/d. The size of adenoma remains same and is associated with increases in GH levels. As the drug is new, its long term safety has not been established. Cholelithiasis has been observed with its long term use.

Current recommendations suggest the use of this agent in patients who fail or are intolerant to surgical and medical therapies, as well as those with very high IGF-1 levels (> 900 ng/mL) or those who experience worsening of glucose tolerance after use of somatostatin analogs.

C. Radiation therapy
RT is indicated in patients not in remission or who have relapsed on medical management. It takes several years to get complete normalisation of elevated GH/IGF1 levels following radiotherapy. Medical therapy may be continued awaiting the results of radiotherapy. Medical therapy should be withdrawn every 6 to 12 months for evaluation of endogenous GH secretion (serum IGF-I and OGTT) and development of any new pituitary hormone deficiencies.

Radiotherapy is similar as for other pituitary adenomas.