Pituitary transsphenoidal microsurgery is the treatment of choice for patients with acromegaly. Many patients have an apparent surgical cure and a remission in all clinical symptoms but continue to have a mildly elevated serum GH or IGF-1 postoperatively. If no residual tumor is apparent on MRI, the patient may elect to be monitored closely, rather than embark on adjuvant medical therapy that is expensive and carries its own risks.
A. Pituitary Microsurgery
Transsphenoidal pituitary surgery achieves a remission in about 70% of patients followed over 3 years. With tumors smaller than 2 cm and GH levels below 50 ng/mL, transsphenoidal pituitary surgery is successful in 80% of patients. Extrasellar extension of the pituitary tumor, particularly cavernous sinus invasion, reduces the likelihood of surgical cure. Transsphenoidal surgery is usually well tolerated, but complications occur in about 12% of patients, including infection, cerebrospinal fluid (CSF) leak, and hypopituitarism. Transsphenoidal pituitary surgery may be difficult in patients with McCune-Albright syndrome because of fibrous dysplasia of the skull base.
Postoperatively, GH levels fall immediately. With successful surgery, serum GH levels are controlled, defined as a serum GH nadir below 0.4 mcg/L (ultrasensitive assay) after an oral glucose load. Serum IGF-1 levels return to the reference range but testing must be done at least 12 weeks after surgery. Fluid and electrolyte disturbances occur in most patients; diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting. Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. It is treated with free water and hypotonic fluid restriction. It is prudent to monitor serum sodium levels postoperatively. Diaphoresis and carpal tunnel syndrome often improve within a day after surgery.
Corticosteroids are administered perioperatively and tapered to replacement doses over 1 week; hydrocortisone is discontinued and a cosyntropin stimulation test is performed about 6 weeks after surgery. At that time, the patient is screened for secondary hypothyroidism (by a serum FT4) and secondary hypogonadism.
Acromegalic patients with an incomplete biochemical remission after pituitary surgery may benefit from medical therapy with dopamine agonists, somatostatin analogs, tamoxifen, or pegvisomant.
Cabergoline is the oral dopamine agonist of choice. It is most successful for tumors that secrete both PRL and GH but can also be effective for patients with normal serum PRL levels. Cabergoline may be tried as monotherapy for patients with serum IGF-1 levels above normal but less than 2.5 times the upper limit of normal. Cabergoline will shrink one-third of acromegaly-associated pituitary tumors by more than 50%. It appears to be safe during pregnancy. The initial dose is 0.25 mg orally twice weekly, which is gradually increased to a maximum dosage of 1 mg three times weekly (based on serum GH and IGF-1 levels). Side effects of cabergoline include nausea, fatigue, constipation, abdominal pain, and dizziness (see Hyperprolactinemia).
Octreotide LAR and lanreotide are long-acting somatostatin analogs that are given by monthly subcutaneous injection. They can achieve serum GH levels below 2 ng/mL in 79% of patients and normal serum IGF-1 levels in 53% of patients. Pasireotide is another long-acting somatostatin analog that is more effective at suppressing GH secretion in resistant patients; however, hyperglycemia is common and distribution is restricted in the United States. Octreotide LAR is given at a dose of 20–40 mg intragluteally every 4 weeks. Lanreotide is given by subcutaneous intragluteal injection at a dosage of 60–120 mg every 4 weeks. Whichever preparation is used, the dosage can be adjusted to achieve serum GH levels under 2 ng/mL. Headaches often improve, and tumor shrinkage of about 30% may be expected. Acromegalic patients with pretreatment serum GH levels exceeding 20 ng/mL are less likely to respond to octreotide or lanreotide therapy. Both appear to be safe during pregnancy. Side effects are experienced by about one-third of patients and include injection site pain, loose acholic stools, abdominal discomfort, or cholelithiasis. All somatostatin analogs are expensive and must be continued indefinitely or until other treatment has been effective.
Raloxifene is a selective estrogen receptor modulator (SERM) that may be useful for persistent acromegaly in men and in women who are postmenopausal or who have had breast cancer. Raloxifene (60 mg orally twice daily) does not reduce serum GH levels but normalizes serum IGF-1 levels in 46% of patients. Serum testosterone levels increase in men.
Pegvisomant, a GH receptor antagonist, is given by daily subcutaneous injection. It blocks hepatic IGF-1 production but does not shrink GH-secreting tumors. Pegvisomant therapy produces symptomatic relief and normalizes serum IGF-1 levels in over 90% of patients. Patients need to be monitored carefully for growth of the pituitary tumor with visual field examinations, GH levels, and MRI scanning of the pituitary. The starting dosage is 10 mg subcutaneously daily. The maintenance dosage can be increased by 5–10 mg every 4–6 weeks, based on serum IGF-1 levels and liver transaminase levels; the maximum dosage is 40 mg subcutaneously daily. It appears to be safe during pregnancy. Pegvisomant has rarely caused hepatitis. Other adverse effects include edema, flu-like syndrome, nausea, and hypertension. Lipohypertrophy can occur at injection sites, so injection sites must be diligently rotated and inspected. In acromegalic diabetics, hypoglycemic drug doses are reduced to avoid hypoglycemia during pegvisomant therapy. The effectiveness of pegvisomant is reduced by coadministration of opioids. Pegvisomant is detected in some GH assays, which could overestimate serum GH levels. Pegvisomant is extremely expensive.
C. Stereotactic Radiosurgery
Acromegalic patients who do not achieve a complete remission with transsphenoidal surgery or medical therapy may be treated with one or a combination of three types of stereotactic radiosurgery: linear accelerator (eg, Cyberknife), gamma knife radiosurgery, and proton beam radiosurgery. Following any pituitary radiation therapy, patients are advised to take lifelong daily low-dose aspirin because of the increased risk of small-vessel stroke. Stereotactic radiosurgery to pituitary tumors causes anterior hypopituitarism in 35–60% of patients within 5 years, so patients must have regular monitoring of their pituitary function.