Symptoms

• Headache and compromised visual function (loss of peripheral vision and blurred vision) caused by the actual tumor mass and its close proximity to the optic structures.

• Loss of other hormonal functions (i.e., LH, FSH, TSH, and ACTH) caused by massive tumor size compressing the anterior pituitary lobe.

• Absence of regular menstrual periods (amenorrhea), impotence, and decreased libido caused by disruption of the gonadotropin secretion.

• Excessive sweating, joint pain, nerve pain, and abnormal neurologic sensations (paresthesias) related to elevated GH and IGF-I levels.

Signs

• Coarsening of facial features

• Increased hand volume

• Increased ring and shoe size

• Increased spacing between teeth

• Increased acne/oily skin

• Enlarged tongue

• Deepening of voice

• Thick, irregular, patchy skin discoloration

• Enlarged nose, lips, and forehead (frontal bossing)

• Abnormal protrusion of the mandible (prognathia)

• Inappropriate secretion of breast milk (galactorrhea)

• Abnormal enlargement of various organs (organomegaly) such as liver, spleen, and heart

• Carpal tunnel syndrome caused by nerve compression from the swollen tissue Laboratory Tests

• GH level greater than 1 ng/mL (1 mcg/L) following an OGTT and elevated IGF-I level compared with age- and sex-matched control values

• Glucose intolerance may be present in up to 50% of patients Additional Clinical Sequelae

• Cardiovascular diseases: hypertension, coronary heart disease, cardiomyopathy, left ventricular hypertrophy, and arrhythmia

• Osteoarthritis and joint damage develop in up to 90% of patients

• Respiratory disorders and sleep apnea occur in up to 60% of patients

• Type 2 diabetes mellitus develops in 25% of patients

• Increased risk for the development of esophageal, colon, and stomach cancer Other Diagnostic Tests

• Perform MRI examination and CT of the pituitary to locate the tumor and validate the diagnosis.

• Without obvious pituitary tumor but proven acromegaly, measurement of GHRH may be helpful to detect ectopic tumors.

Adapted, from Sheehan AH, Yanovski JA, Calis KA. Pituitary Gland Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy. A Pathophysiologic Approach. 7th ed. New York: McGraw Hill, 2008:1284.

Pharmacologic Therapy

Pharmacologic therapy is often necessary for patients in whom surgery is not an option. Somatostatin analogs, GH receptor antagonists, and dopamine agonists are the primary pharmacologic therapies used for the management of acromegaly (Table 46-2). Pharmacologic therapy avoids hypopituitarism and other surgical risks.

Somatostatin Analog (GH-Inhibiting Hormone)

Somatostatin analogs are the mainstay of pharmacotherapy for the treatment of acromegaly when surgery is contraindicated or has failed. These agents mimic endogenous somatostatins and bind to the somatostatin receptors in the pituitary to cause potent inhibition of GH, insulin, and glucagon secretion. Long-term treatment can sustain hormone suppression, alleviate soft-tissue manifestations, and reduce tumor size. Use of the first-generation somatostatin analog, octreotide, is limited by its extremely short duration of action which necessitates frequent injections of at least three times per day. The long-acting preparations of octreotide and lanreotide are considered the cornerstone of therapy due to improved patient adherence and acceptability. Typically, at least a 2-week trial of short-acting octreotide is recommended to determine efficacy and tolerance before switching to a long-acting preparation. The long-acting formulations can be administered every 14 to 28 days. Their efficacy and safety have been demonstrated in long-term studies (up to 9 years with octreotide and 4 years with lan-reotide).16-18 Long-acting octreotide effectively suppresses GH levels and achieves normal IGF-I levels in 67% and 57% of patients, while lanreotide slow-release formulation achieved lower response rates of 48% and 47%, respectively.19 However, the response rate of long-acting octreotide may be overestimated due to differences in subject selection.19 Recent limited data suggested treatment with lanreotide autogel is comparable to lanreotide slow-release and as effective as long-acting octreotide.18 Since somatostatin analogs can achieve substantial relief of clinical symptoms with significant reduction in tumor size,19,20 it is important to monitor patients for tumor recurrence if treatment is discontinued. Due to lack of sufficient data, routine use of presurgical somatostatin analogs is currently not recommended unless a delay in surgery is anticipated.18

FIGURE 46-3. Management of growth hormone-producing adenomas (GH, growth hormone; IGF-I, insulin-like growth factor I.) (Adapted from Ref. 3.)

Somatostatin analogs are generally well tolerated. Common adverse effects include transient GI disturbances such as diarrhea, abdominal pain, flatulence, constipation, and nausea.18 These adverse GI effects usually subside within the first 3 months of therapy. Somatostatin analogs inhibit gallbladder contractility and decrease bile secretion; therefore, their major adverse effect is development of biliary sludge and asymptomatic gallstones (cholelithiasis). Biliary sludge is a predisposing factor for the high incidence of cholelithiasis observed in up to 20% of patients.5 Development of gallstones typically occurs in patients treated for 12 months or longer and is unrelated to age, gender, or dose. Somatostatin analog-induced gallstones should be managed according to standard guidelines.5 Additionally, somatostatin analogs may alter the balance of counterregulatory hormones (i.e., glucagon, insulin, and GH), resulting in either hypoglycemia or hyperglycemia.18 Octreotide also may suppress pituitary release of TSH, leading to decreased thyroid hormone secretion and subsequent hypothyroidism in 12% of treated patients. Close monitoring of thyroid function and glucose metabolism is recommended. Sinus bradycardia, conduction abnormalities, and arrhythmias have been reported with octreotide and lanreotide. Due to the potential adverse effects of the somatostatin analogs, concomitant use with insulin, oral hypoglycemic agents, ^-blockers, or calcium channel blockers may require careful dosage adjustment. Somatostatin analogs also may alter the bioavailability and elimination of cyclosporine, and monitoring of cyclosporine serum concentration is necessary.

Table 46-2 Comparison of Various Drugs for Treatment of Acromegaly

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GH-Receptor Antagonist

GH-receptor antagonist represents a novel approach to the treatment of acromegaly. Pegvisomant is the only genetically engineered GH-receptor antagonist that blocks the action of GH. The effects of pegvisomant work independently of tumor characteristics, somatostatin, and dopamine receptors.21 Up to 97% of acromegalic patients treated with pegvisomant (10-20 mg/day) achieved normal age-related IGF-I levels and experienced significant improvement in clinical symptoms of GH excess by 1 22 23

year of therapy. In patients previously resistant to somatostatin analog therapy, normal IGF-I concentrations were achieved in 75% of patients treated with pegvi-24

somant and in 69% to 100% of patients treated with pegvisomant and somatostatin 25—27

analog therapy. Pegvisomant therapy may have favorable effects on glucose tolerance (the body's ability to metabolize glucose) and insulin sensitivity (capacity of

cells to respond to insulin). However, use of pegvisomant is associated with significant dose-dependent increases in GH despite the declining IGF-I levels.22,23 The dose-dependent increase in GH is troubling because it has been suggested that persistent elevation of GH levels may be indicative of tumor growth. Thus, careful monitoring with periodic imaging scans is indicated, especially when administering pegvisomant to patients at risk for visual damage from large tumors that may impinge on the optic chiasm. Pegvisomant is indicated for patients who do not tolerate or fail other treatment options, or for those with extremely elevated IGF-I levels (greater than 900 ng/mL or 900 mcg/L).3 Long-term efficacy and safety profiles of pegvisomant in acromegaly remain to be established. Available data suggest that pegvisomant appears well-tolerated with minimal adverse effects such as self-limiting injection-site reactions, nausea, diarrhea, infection, and flu-like symptoms. Approximately 17% of patients who receive pegvisomant develop non-neutralizing anti-GH antibodies. Although the long-term consequences are unknown, the presence of antibodies does not appear to affect the efficacy of pegvisomant. Cases of hepatotoxicity have been repor-

22 23

ted in clinical trials, with a higher risk observed in diabetics receiving combined

pegvisomant and somatostatin analogs. Therefore, obtain baseline levels oftransam-inases, total bilirubin, and alkaline phosphatase prior to initiating therapy and periodically thereafter. Caution should be used when administering pegvisomant to patients with elevated liver function tests, and therapy should be discontinued in the presence of clinical signs and symptoms of hepatic injury.

Dopamine Agonists

Dopamine is one of the neuro-transmitters that can increase GH secretion in healthy adults. However, dopamine agonists administered to patients with acromegaly exert the opposite effect and suppress GH release from the tumor. The first dopamine agonist for acromegaly, bromocriptine, achieved normal IGF-I levels in fewer than 10% of patients and was associated with significant adverse effects, including nausea, dizziness, and headaches.10 The large doses of bromocriptine required to achieve the desired response often are associated with dose-limiting toxicity, such as GI discomfort and orthostatic hypotension. Cabergoline, the selective long-acting agonist with improved tolerability, effectively can normalize IGF-I levels in 35% of patients and reduce GH levels in 44% of patients.28 Acromegalic patients with coexisting hyperpro-lactinemia also had a more favorable response to cabergoline, with 50% of patients achieving normal IGF-I levels, 56% GH suppression, and 65% tumor shrinkage.28 Although orally administered dopamine agonists are the least expensive medical therapy for managing acromegaly, the major disadvantage is their relative lack of efficacy compared with existing therapeutic options. Dopamine agonists may be appropriate for patients with mildly elevated IGF-I levels who have GH and prolactin cose-creting tumors.3

Radiation Therapy

Radiation therapy is an important adjunctive therapy in patients with residual GH excess following surgery or pharmacologic therapy. Treatment involves the use of radiation to destroy rapidly growing tumor cells and often results in a reduction in tumor size. A major complication resulting from radiation therapy is hypopituitarism, requiring lifelong hormone replacement. There is also the potential for optic nerve damage if the pituitary tumor is near the optic tracts. Radiation therapy may take 10 to 20 years before its full effects become evident.10 Owing to delay in onset of radiation effectiveness, pharmacologic therapy often is indicated as bridge therapy. Men and women who desire to have children should be warned that pituitary irradiation therapy may impair fertility.

Outcome Evaluation

• Following a baseline evaluation, monitor patients regularly for symptom relief. See

Acromegaly: Patient Care and Monitoring text Box

• Lifelong biochemical assessment is critical for determining therapeutic outcomes.

Although some patients may experience a rapid decline in GH levels following transsphenoidal microsurgery, stabilization of IGF-I levels usually occurs 3 months following surgery but rarely may be delayed for up to 12 months. Measure GH and IGF-I levels 3 months postoperatively to assess treatment response.6

• Because up to 10% of pituitary tumors may recur within 15 years following sur-gery,6 continual postoperative monitoring is recommended.

• For patients treated with somatostatin analogs, assess baseline fasting blood glucose, thyroid function tests, and heart rate. Thereafter, periodically monitor patients for adverse reactions such as GI disturbances, glucose intolerance, signs and symptoms of thyroid abnormalities, bradycardia, and arrhythmias in patients receiving long-term somatostatin analogs. Reevaluate IGF-I and GH levels at 3-month intervals to determine therapeutic response. Because the frequency of symptomatic gallstones associated with somatostatin analogs varies among studies, the need for routine ultrasound evaluation remains controversial. However, ultrasonography of the gallbladder would be indicated if the patient develops symptoms of biliary abnormalities.

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