Acromegaly is a pathologic condition characterized by excessive production of GH. This is a rare disorder with prevalence ranging between 2.8 and 13.7 cases per 100,000 and incidence rates ranging between 0.2 and 1.1 cases per 100,000 people.6 Gigantism, which is rarer than acromegaly, is the excess secretion of GH prior to epiphyseal closure in children.7 Patients diagnosed with acromegaly have a two- to threefold increase in mortality, usually related to cardiovascular, respiratory, or neoplastic disease.7–10 Most patients are middle-aged at the time of diagnosis, and this disorder does not appear to affect one sex to a greater extent than the other.6 The most common cause of excess GH secretion in acromegaly is a GH-secreting pituitary adenoma, accounting for over 95% of all cases.7 Rarely, acromegaly is caused by ectopic GH-secreting adenomas, GH cell hyperplasia, excess GHRH secretion, or is a manifestation of multiple endocrine neoplasia syndrome type 1, McCune–Albright syndrome, or the Carney complex, all very rare hypersecretory endocrinopathies.7–9
The clinical signs and symptoms of acromegaly develop gradually over an extended period of time. The changes in physical appearance caused by GH excess are slow and subtle to develop. Thus, most patients are not diagnosed with acromegaly until 7 to 10 years after the presumed onset of excessive GH secretion.9 Excessive secretion of GH and IGF-1 adversely affects several organ systems. Almost all patients with acromegaly will present with physical signs and symptoms of soft-tissue overgrowth. Table e94-2 summarizes the classic clinical presentation of patients with acromegaly.7–9 Some patients with acromegaly present with only a few of these classic signs and symptoms, making recognition of this disease extremely difficult.
TABLE e94-2Clinical Presentation of Acromegaly |Favorite Table|Download (.pdf) TABLE e94-2 Clinical Presentation of Acromegaly
The patient will experience slow development of soft-tissue overgrowth affecting many body systems. Signs and symptoms may gradually progress over many years.
The patient may complain of symptoms related to local effects of the GH-secreting tumor, such as headache and visual disturbances. Other symptoms related to elevated GH and IGF-1 concentrations include excessive sweating, neuropathies, joint pain, and paresthesias
The patient may exhibit coarsening of facial features, increased hand volume, increased ring size, increased shoe size, an enlarged tongue, and various dermatologic conditions
The patient’s GH concentration will be more than 1 mcg/L (>45 pmol/L) following an OGTT, and IGF-1 serum concentrations will be elevated. Glucose intolerance may be present in up to 50% of patients.
Common Comorbid Conditions
Cardiovascular diseases such as hypertension, coronary heart disease, cardiomyopathy, and left ventricular hypertrophy are common in patients with acromegaly
Osteoarthritis and joint damage develop in up to 90% of acromegalic patients
Respiratory disorders and sleep apnea occur in up to 60% of acromegalic patients
Type 2 diabetes develops in approximately 25% of acromegalic patients
Patients with acromegaly may be at higher risk of developing esophageal, colon, and stomach cancer
The diagnosis of acromegaly is based on a combination of diagnostic tests and clinical signs and symptoms. Random measures of plasma GH levels are not dependable because of the pulsatile pattern of release. However, some clinicians exclude diagnosis of acromegaly in the presence of a random GH below 0.4 mcg/L (<18 pmol/L) and IGF-1 that is normal for age and sex.7–9 The oral glucose tolerance test (OGTT) is commonly used as an important diagnostic tool. Postprandial hyperglycemia inhibits the secretion of GH for at least 1 to 2 hours. Therefore, an oral glucose load would be expected to suppress GH concentrations. However, patients with acromegaly continue to secrete GH during the OGTT. Because GH stimulates the production of IGF-1, serum IGF-1 concentration is often measured as the initial screening test in the diagnosis of acromegaly. Circulating IGF-1 is cleared from the body at a much slower rate than is GH, and measurements can be collected at any time of the day to identify patients with GH excess.7–9 Current criteria for the diagnosis of acromegaly include failure of GH suppression to less than 1 mcg/L (<45 pmol/L) following an OGTT in the presence of elevated IGF-1 serum concentrations (strong recommendation, moderate quality of evidence).7,8,11 With the development of more sensitive GH and IGF-1 assays, the American Association of Clinical Endocrinologists (AACE) suggests lowering the cutoff for GH suppression to less than 0.4 mcg/L (<18 pmol/L), although other groups still support a cutoff of less than 1 mcg/L based on concerns of requisite sensitivity of many assays.7,8,11 Insulin-like growth factor 1 binding protein 3 (IGFBP-3) is positively regulated by GH and binds to circulating IGF-1 with high affinity. This test may prove useful in the future in monitoring response to therapy but, at present, AACE does not recommend IGFBP-3 measurement for the purpose of clinical management.8 Computed tomography and magnetic resonance imaging (MRI) of the pituitary are important diagnostic tests to confirm the presence of a pituitary adenoma.7,8,11
The primary treatment goals for patients diagnosed with acromegaly are to reduce GH and IGF-1 concentrations, improve the clinical signs and symptoms of the disease, and decrease mortality.7,8,11–14 Many clinicians define biochemical control of acromegaly as suppression of GH concentrations to less than 1 mcg/L (<45 pmol/L) after a standard OGTT in the presence of normal IGF-1 serum concentrations. However, some experts have proposed a lower cutoff GH value of 0.4 mcg/L (18 pmol/L) due to the availability of more sensitive test methods.12 The treatment of choice for most patients with acromegaly is transsphenoidal surgical resection of the GH-secreting adenoma (strong recommendation, moderate quality evidence).7,8,11–13 Postsurgical cure rates have been reported to range from 50% to 90%, depending on the type of adenoma and the expertise of the neurosurgeon.7,8,13 Complications of transsphenoidal surgery are relatively infrequent and include cerebrospinal fluid leak, meningitis, arachnoiditis, diabetes insipidus, and pituitary failure.8 For patients who are poor surgical candidates, those who have not responded to surgical or medical interventions, or others who refuse surgical or medical treatment, radiation therapy may be considered. However, radiation therapy may require several years before the symptoms of acromegaly are relieved.
Because neither radiation therapy nor surgery will cure all patients with acromegaly, adjuvant drug therapy is often needed to control symptoms.7,8,11,12 Figure e94-2 shows a treatment algorithm for the management of acromegaly.7,8
Treatment algorithm for acromegaly. (DA, dopamine agonist; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; SRL, somatostatin analog; SRT, stereotactic radiotherapy.) (Reprinted, with permission, from Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933–3951. Copyright 2014, The Endocrine Society.)
Drug therapy should be considered primary therapy for patients with acromegaly who prefer medical therapy, are poor surgical candidates, or when there is a poor likelihood of surgical success. In addition, drug therapy should be considered as adjunctive therapy in the presence of persistent disease after surgery (strong recommendation, high-quality evidence).7,8 The most common pharmacologic treatment options include dopamine agonists, somatostatin analogs, and the GH-receptor antagonist pegvisomant. Dopamine agonists such as bromocriptine and cabergoline are effective in a small subset of patients. Their principal advantages are oral administration and lower cost. Somatostatin analogs are more effective than dopamine agonists, reducing GH concentrations and normalizing IGF-1 in approximately 50% to 60% of patients. Pegvisomant, a GH-receptor antagonist, is highly effective in normalizing IGF-1 concentrations in up to 97% of patients in the first year and in 60% over 5 years.
In normal healthy adults, dopamine agonists cause an increase in GH production. However, when these agents are given to patients with acromegaly, there is a paradoxical decrease in GH production. The greatest clinical experience with the use of dopamine agonists in acromegaly has been with bromocriptine or cabergoline. Other agents such as pergolide, quinagolide, and lisuride also have been used but are not available in the United States. Bromocriptine and cabergoline are semisynthetic ergot alkaloids that act as dopamine-receptor agonists. Most trials assessing the efficacy of bromocriptine in the treatment of acromegaly were conducted in the 1970s and early 1980s and determined that bromocriptine was effective in suppressing serum GH levels to less than 5 mcg/L (<225 pmol/L) in approximately 20% of patients.15 While only 10% of patients experience a normalization of IGF-1 concentrations with bromocriptine therapy, more than 50% of patients treated with bromocriptine experience improvement in symptoms of acromegaly.8,15 Cabergoline is used more commonly than bromocriptine.8 A meta-analysis of 15 studies concluded that cabergoline as monotherapy was effective in normalizing IGF-1 levels in 34% of patients and resulted in normalization of IGF-1 levels in 52% of patients when added to a somatostatin analog in those unresponsive to somatostatin analog monotherapy.16
In the United States, bromocriptine is commercially available as 0.8- and 2.5-mg oral tablets and 5-mg oral capsules. The 0.8-mg tablet is only approved for adjunctive therapy in type 2 diabetes mellitus. In acromegalic patients, significant reductions in GH concentrations are observed within 1 to 2 hours of oral dosing. This effect persists for at least 4 to 5 hours. An overall clinical response in acromegalic patients typically occurs after 4 to 8 weeks of continuous bromocriptine therapy. For treatment of acromegaly, bromocriptine is initiated at a dose of 1.25 mg (1/2 of a 2.5-mg tablet) at bedtime and is increased by 1.25-mg increments every 3 to 4 days as needed. Doses as high as 86 mg/day have been used for treatment of acromegaly, but clinical studies have shown that dosages more than 20 to 30 mg daily do not offer additional benefits in the suppression of GH. When used for treatment of acromegaly, the duration of action of bromocriptine is shorter than that for treatment of hyperprolactinemia. Therefore, the total daily dose of bromocriptine should be divided into three or four doses.
Cabergoline is commercially available as 0.5-mg tablets. Use in acromegaly is considered off-label. Dosing is typically initiated at 0.5 mg twice weekly and increased as needed to 0.5 mg every other day. Doses up to 7 mg/wk (0.5 mg twice daily) have been used in clinical trials.
The most common adverse effects of dopamine agonist therapy include central nervous system (CNS) symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue. Gastrointestinal (GI) effects such as nausea, abdominal pain, or diarrhea also are very common. Some patients may need to take dopamine agonists with food to decrease the incidence of adverse GI effects. Most adverse effects are seen early in the course of therapy and tend to decrease with continued treatment.8,15 Dopamine agonists may cause thickening of bronchial secretions and nasal congestion. Rare cases of psychiatric disturbances, pleural diseases, and an erythromelalgic syndrome (painful paroxysmal dilation of the blood vessels in the skin of the feet and lower extremities) have been reported with dopamine agonist use. These conditions appear to be associated with higher doses and prolonged duration of therapy.8,15
Dopamine agonists are not FDA-approved for use during pregnancy. However, surveillance of women who took dopamine agonists throughout pregnancy does not suggest that dopamine agonists are associated with an increased risk for birth defects.17 If a woman becomes pregnant while taking dopamine agonists, the risks and benefits of therapy should be discussed with the patient. In most cases, the benefits of successful therapy outweigh the risks, and dopamine agonist therapy should be continued if symptoms have improved and GH concentrations have been reduced.
Given the potential cost advantages and convenience of oral administration, dopamine agonists are often considered for treatment of acromegaly prior to initiation of somatostatin analogs. The Endocrine Society guidelines suggest a trial of a dopamine agonist in acromegalic patients with mild signs and symptoms and modest elevations in serum IGF-1 (weak recommendation, low-quality evidence).7 However, long-acting somatostatin analogs are considered a more attractive first-line treatment option for acromegaly.
Octreotide, lanreotide, and pasireotide are long-acting somatostatin analogs that are more potent in inhibiting GH secretion than endogenous somatostatin.18 The Endocrine Society suggests somatostatin analogs as initial adjuvant medical therapy in patients with significant disease (weak recommendation, low-quality evidence) and as primary therapy in patients who cannot be cured by surgery or are poor surgical candidates (weak recommendation, moderate-quality evidence).7 These agents also suppress the LH response to GnRH; decrease splanchnic blood flow; and inhibit secretion of insulin, vasoactive intestinal peptide (VIP), gastrin, secretin, motilin, serotonin, and pancreatic polypeptide. Pasireotide is a somatostatin analog that has a broader affinity for somatostatin receptor subtypes than octreotide or lanreotide and this may result in greater GH inhibition. Pasireotide is also effective for octreotide or lanreotide-resistant adenomas.18
Octreotide (Sandostatin) injection is commercially available in the United States for subcutaneous or IV administration. A long-acting intramuscular formulation of octreotide (Sandostatin LAR) is available for monthly administration. An investigational oral formulation of octreotide administered as monotherapy was effective in a phase III study maintaining control of IGF-1 and GH serum concentrations over 13 months in 60% of patients previously well controlled with an injectable formulation.19 In addition to the treatment of acromegaly, octreotide has many other therapeutic uses, including the treatment of carcinoid tumors, vasoactive intestinal peptide-secreting tumors (VIPomas), GI fistulas, variceal bleeding, diarrheal states, and irritable bowel syndrome.
The efficacy of octreotide for treatment of acromegaly was initially determined by two major multicenter trials.20,21 These studies demonstrated that drug therapy with octreotide suppresses mean serum GH concentrations to less than 5 mcg/L (<225 pmol/L) and normalizes serum IGF-1 concentrations in 50% to 60% of patients and reduces the clinical signs and symptoms of acromegaly. In a 6-month multicenter trial, 70% of patients experienced significant relief of headaches.21 In some patients, relief of headache symptoms occurred within minutes of octreotide administration. In addition, middle-finger circumference was reduced significantly, and 50% to 75% of patients experienced improvement in symptoms of excessive perspiration, fatigue, joint pain, and cystic acne. Long-term follow-up of patients with acromegaly treated with octreotide LAR for up to 9 years showed therapy to be safe and effective.22 Octreotide also has been shown to improve the cardiovascular manifestations of acromegaly and to halt pituitary tumor growth, with some patients experiencing tumor regression.23 Shrinkage of pituitary tumor mass occurs in approximately 50% of patients.24
The pharmacodynamic effects of long-acting octreotide are similar to those of subcutaneously administered octreotide. Single monthly doses of long-acting octreotide have been shown to be at least as effective as daily doses of subcutaneous octreotide administered in divided doses three times daily in normalizing IGF-1 levels and maintaining suppression of mean serum GH concentrations.25 Trials evaluating the efficacy of long-acting octreotide in patients who previously responded to subcutaneously administered octreotide have reported sustained suppression of GH concentrations to less than 5 mcg/L (<225 pmol/L) and normalization of IGF-1 in patients following 1 year of therapy.25
Response to therapy with octreotide is related to the presence and increased quantity of functioning somatostatin receptors located in the pituitary adenoma. Identification of patients who will most likely respond to octreotide, prior to initiation of long-term therapy, is important when considering the high cost of this medication and the inconvenience of subcutaneous or intramuscular drug administration. Suppression of serum GH concentrations after a single 50-mcg dose of octreotide has been used to predict a favorable long-term response to octreotide therapy but the reliability of this test is not universally accepted.7,26
The initial dose of octreotide for treatment of acromegaly is usually 100 mcg administered three times daily followed by either titration to a maximum of 1,500 mcg/day or transition to long-acting octreotide.8 Some clinicians recommend a starting dose of 50 mcg every 8 hours, then increasing the dose to 100 mcg every 8 hours after 1 week, to improve the patient’s tolerance of adverse GI effects. The dose can be increased by increments of 50 mcg every 1 to 2 weeks based on mean serum GH and IGF-1 concentrations. Patients who experience a significant rise in GH prior to the end of the 8-hour dosing interval may benefit from decreasing the dosing interval to every 4 to 6 hours. Although doses as high as 1,500 mcg/day have been used, doses greater than 600 mcg daily generally do not offer additional benefits, and most patients are adequately managed with 100 to 200 mcg three times daily.8 Patients who have been maintained on subcutaneous octreotide for at least 2 weeks and have shown response to therapy can be converted to the long-acting depot form of octreotide. The initial dose of long-acting octreotide is 20 mg administered intramuscularly in the gluteal region every 28 days. Steady-state serum concentrations are not obtained until after 3 months of therapy. Therefore, dosage adjustments for long-acting octreotide should not be considered until after the 3rd dose. Some patients may require additional subcutaneous injections during the initial dose-titration phase in order to control symptoms. In patients who achieve more than 50% reduction in GH levels, the dose should be increased to 30 mg every 4 weeks. Some patients may require as much as 60 mg every 4 weeks.27
Lanreotide (Somatuline Depot) is commercially available in the United States for monthly, deep subcutaneous administration. In addition to acromegaly, lanreotide is also indicated for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and carcinoid syndrome. The efficacy of lanreotide for the treatment of acromegaly has been evaluated in several prospective multicenter clinical trials involving treatment-naïve and treatment-experienced patients who were switched from intramuscular octreotide LAR or intramuscular lanreotide LA to monthly deep subcutaneous lanreotide.28 These studies have determined that deep subcutaneous lanreotide suppresses mean serum GH concentrations to less than 5 mcg/L (<225 pmol/L) and normalizes serum IGF-1 concentrations to a similar extent as octreotide LAR and lanreotide LA. A 4-year follow-up of 23 patients treated with monthly deep subcutaneous lanreotide reported the drug to be well tolerated during long-term therapy with mean serum GH concentrations less than 5 mcg/L (<225 pmol/L) in 62% of patients and normalization of serum IGF-1 concentrations in 43% of patients.29 Analyses of trials investigating the effects of lanreotide on pituitary tumor mass have shown shrinkage in the majority of patients, and the response appears to be more prevalent in treatment-naïve patients and in patients with macroadenomas.28,30 Well-designed trials directly comparing the efficacy of intramuscular octreotide LAR to deep subcutaneous lanreotide are currently lacking. However, these two agents are generally regarded to have comparable efficacy.7,8
Lanreotide (Somatuline Depot) is commercially available in the United States as 60-, 90-, and 120-mg prefilled syringes. In contrast to octreotide LAR and pasireotide, lanreotide does not need to be reconstituted prior to administration. The initial recommended dose of lanreotide is 90 mg given by deep subcutaneous injection in the superior external quadrant of the buttock every 28 days. Injection sites should be alternated between the left and right side. The initial dose should be reduced to 60 mg every 28 days for patients with moderate or severe renal or hepatic impairment. After 3 months of therapy, the dose may then be titrated and/or frequency extended, based on serum GH concentrations, serum IGF-1 concentrations, and control of signs and symptoms of acromegaly.28 Patients well controlled on lanreotide 60 or 90 mg every 28 days may consider an extended dosing interval of lanreotide 120 mg every 6 to 8 weeks. Increases in drug frequency greater than every 28 days or higher than 120 mg may be recommended for patients with partial responses to lanreotide.31
Pasireotide (Signifor LAR) for the treatment of acromegaly is commercially available in the United States in the form of a monthly intramuscular injection. Another formulation of pasireotide (Signifor) is approved for treatment of Cushing disease as a twice daily subcutaneous injection. The efficacy of the long-acting pasireotide formulation has been evaluated in both drug-naïve patients and those inadequately controlled on long-acting octreotide or lanreotide.32–35 In drug-naïve patients treated for 12 months, pasireotide suppressed mean serum GH concentrations to less than 2.5 mcg/L and normalized serum IGF-1 concentrations in 38% compared to 23% with octreotide.33 An extension study of up to 25 months noted long-term biochemical control (GH < 2.5 mcg/L and normal IGF-1) in 48% with pasireotide compared with 45% with octreotide.34 In patients inadequately controlled with octreotide or lanreotide, pasireotide resulted in biochemical control (GH < 2.5 mcg/L and normal IGF-1) in 15% to 20% of patients treated for 24 weeks.35
The initial recommended dose of pasireotide is 40 mg given by intramuscular injection every 28 days. The initial dose should be reduced to 20 mg every 28 days for patients with moderate or severe hepatic impairment. After 3 months of therapy, the dose may be titrated based on serum GH concentrations, serum IGF-1 concentrations, and control of signs and symptoms of acromegaly. Doses of pasireotide exceeding 60 mg every 28 days are not recommended.32
The most common adverse effects of somatostatin analog therapy are GI disturbances such as diarrhea, nausea, abdominal cramps, malabsorption of fat, and flatulence.25,28,32 GI adverse effects occur in approximately 75% of patients but usually subside within 10 to 14 days of continued treatment. Octreotide can cause injection-site pain (4%-31%), conduction abnormalities and arrhythmias (9%), subclinical hypothyroidism (2%-12%), biliary tract disorders (4%-50%), and abnormalities in glucose metabolism (2%-18%). Lanreotide has been associated with injection-site reactions (9%), sinus bradycardia (3%), hypertension (5%), biliary tract disorders (20%), and abnormalities in glucose metabolism (7%). While adverse effects with pasireotide are similar to octreotide and lanreotide, the incidence of hyperglycemia is significantly greater (61%-67% vs 25%-30%) often requiring treatment with antidiabetes medications (38%-39% vs 6%).
Somatostatin analogs also inhibit cholecystokinin release and gallbladder motility, predisposing patients to the development of cholelithiasis.36,37 The development of gallstones is a long-term adverse effect of somatostatin analog therapy and is largely dependent on geographic factors, dietary habits, and length of therapy. The incidence of gallstones in patients with acromegaly receiving octreotide and lanreotide increases with the duration of therapy and has been reported to range from 20% to 50%.25,28,32 However, most patients are asymptomatic, and the diagnosis of cholelithiasis usually is made following an ultrasonographic study that is not prompted by patient symptoms. It has been estimated that only 1% of patients will develop symptomatic gallstones during 1 year of octreotide treatment.36 Because somatostatin analog-induced gallstones usually are present without symptoms, prophylactic cholecystectomy or medical therapy with ursodeoxycholic acid is not recommended. A small number of studies have suggested that the incidence of gallstone development may be lower with long-acting octreotide compared to subcutaneous octreotide.25 However, further studies are needed to confirm this observation.
The effect of somatostatin analogs on glucose metabolism in patients with acromegaly is multifactorial. Decreases in serum GH concentrations induced by somatostatin analogs should result in decreased hepatic gluconeogenesis and increased insulin-receptor sensitivity. However, somatostatin analogs also decrease insulin secretion and increase IGFBP-1, which is known to inhibit the insulin-like effects of IGF-1. In addition, somatostatin analogs delay the GI absorption of glucose, which may further alter glucose metabolism in patients with acromegaly.38 Patients with diabetes should be actively monitored and glucose lowering medications adjusted accordingly.39 Risk factors associated with worsening glucose tolerance included female sex and elevated baseline insulin concentrations. Although somatostatin analogs have a beneficial effect on glucose tolerance in most patients, glucose determinations should be obtained frequently in the early stages of therapy.
Growth Hormone Receptor Antagonist
Pegvisomant (Somavert) is a genetically engineered GH derivative that binds to, but does not activate, GH receptors and inhibits IGF-1 production. This agent is different from other medications used in the management of acromegaly because it does not inhibit GH production; rather, it blocks the physiologic effects of GH on target tissues. Therefore, GH concentrations remain elevated during therapy, and response to treatment is evidenced by a reduction in IGF-1 concentrations. Unlike somatostatin analogs, the pharmacologic activity of pegvisomant does not depend on the presence and quantity of somatostatin receptors in the pituitary tumor.40 Studies evaluating the efficacy of pegvisomant have reported a dose-dependent normalization of IGF-1 concentrations in 54% to 89% of patients after 12 weeks of therapy and in 97% of patients after 1 year of therapy.40,41 Significant improvements in the clinical signs and symptoms of acromegaly were reported and persisted throughout the 1-year treatment period.41 An ongoing, international postmarketing surveillance registry (ACROSTUDY) reported normalization of IGF-1 serum concentrations in 63% of patients treated with pegvisomant for 5 years. Investigators note that failure to maintain IGF-1 normalization may reflect suboptimal dosing or more advanced disease than reported in the original studies.42
Adverse effects include injection-site pain, GI complaints such as nausea and diarrhea, and flu-like symptoms. Significant elevations in hepatic aminotransferase concentrations, which are generally reversible after discontinuation of the drug, have been reported.43 Hepatic function tests should be monitored very closely during therapy as outlined in the product labeling and the drug should be used with caution in patients with baseline elevations in hepatic aminotransferase concentrations. GH concentrations may increase significantly during the first 6 months of pegvisomant therapy. Tumor growth has been reported in a small number of patients and there are theoretical concerns that the lack of GH feedback regulation on tumors that lead to persistently elevated GH concentrations may stimulate tumor growth or result in other long-term adverse effects. Results of the ongoing ACROSTUDY suggest that the rate of tumor growth is comparable to the background rate in acromegaly, and the incidence of hepatic aminotransferases greater than three times upper limit of normal is low (2.5%).42
Pegvisomant is commercially available in the United States for daily subcutaneous use. It is recommended by the manufacturer that the initial 40-mg loading dose be administered under direct supervision by physician but some authors note this is rarely done. Subsequent doses are self-administered by the patient starting at a dose of 10 mg daily. The dose can be adjusted in 5-mg increments based on serum IGF-1 concentrations every 4 to 6 weeks. The typical maintenance dose is 10 to 30 mg daily. Higher doses (40-60 mg daily) have been reported in patients who are younger, overweight, or have diabetes or high baseline IGF-1 levels.43
Based on high response rates in clinical trials, pegvisomant appears to be among the most effective agent for normalizing IGF-1 serum concentrations. Current guidelines for acromegaly management suggest pegvisomant therapy for patients who have failed to achieve normalization of IGF-1 serum concentrations with other treatments or as the initial adjuvant medical therapy (weak recommendation, low-quality evidence).7,8,11
Several small studies have suggested that combination therapy with somatostatin analogs, dopamine agonists, or pegvisomant may be more effective than monotherapy.7,8 Several of these trials have used doses lower than those typically used for monotherapy in order to reduce the risk of adverse effects. The Endocrine Society recommends the addition of pegvisomant or cabergoline in patients with inadequate response to a somatostatin analog (weak recommendation, low-quality evidence).7 Because of the potential for additive adverse effects, combination therapy should be considered as a therapeutic option only for refractory patients who have not fully responded to monotherapy.7,8
While several biomarkers have been studied in pituitary tumors, the prognostic value of these in predicting response to therapy is still unclear.44 Genetic variability in GH and its receptors have been well-characterized.45 Researchers have investigated patient response to pegvisomant based on GH receptor variants. In patients with exon 3-deleted GH receptors, lower doses and fewer months were needed to obtain IGF-1 normalization.46 However, recommendations regarding how therapy can be individualized based on genetic testing to maximize patient benefit are not yet available.7,8,46
Evaluation of Therapeutic Outcomes
Appropriate monitoring of medical therapy for acromegaly incorporates assessing for control of biochemical targets and clinical symptoms. An age-normalized serum IGF-1 and random GH are used to guide dosing and frequency of administration and it is recommended to periodically assess these parameters as they correlate with disease control. Clinical symptoms that may relate to the tumor size (eg, headaches, visual disturbances) or elevations in GH or IGF-1 (eg, excessive sweating, arthralgia) should also be assessed periodically. Additional laboratory tests to monitor for adverse events include serum glucose, for somatostatin analogs, and hepatic aminotransferases, for pegvisomant.
Acromegaly is a chronic debilitating disease characterized by excess GH secretion most commonly caused by a GH-secreting pituitary adenoma. Transsphenoidal surgical resection of the adenoma is the current treatment of choice for most patients with acromegaly. Patients who are poor surgical candidates may receive radiation therapy or long-term pharmacologic therapy. Drug therapy options within the United States for acromegaly include dopamine agonists, somatostatin analogs, and pegvisomant.