Introduction
Diagnosis
Goals of Therapy
Pharmacologic Therapy
Conclusion
 

Pharmacologic Therapy

Pharmacologic therapy has a role as primary and adjuvant therapy in the treatment of acromegaly. For both, the somatostatin analogs are the first agents of choice for most patients. For patients who are not responsive to these agents, GH receptor antagonists or dopamine agonists are available.

Somatostatin Analogs
Somatostatin analogs work through several mechanisms to reduce GH excesses: 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.[16] These analogs are classified on the basis of their affinity to subtypes of somatostatin receptor (SSTR): SSTR2 is expressed in 96% of tumors, and SSTR5 is expressed in 86% of GH-secreting tumors.[31-33]

Currently, 2 somatostatin analogs are commercially available -- octreotide and lanreotide (Table). Both exhibit a high affinity to SSTR2. Other experimental somatostatin analogs are under investigation for additional subtype selectivity.[32]

Table. Currently Available Somatostatin Analogs[16]
Drug Type Dosing
Octreotide Short-acting Subcutaneous 3 times/day; dose range of 50-500 mcg
Octreotide LAR Long-acting Intramuscular every 28 days; dose range of 10-40 mg
Lanreotide depot* Long-acting Intramuscular every 7-14 days
Lanreotide autogel* Long-acting Deep subcutaneous every 28 days

LAR = long-acting release
*Not available in the United States
The first somatostatin analog available for clinical use was subcutaneously administered octreotide, which requires dosing 3 times per day. A long-acting release (LAR) formulation consists of octreotide enclosed in microspheres of a biodegradable polymer and administered by intramuscular injection every 28 days. A slow-release intramuscular formulation of lanreotide has also been developed but is not available in the United States. A formulation of lanreotide that is subcutaneously administered in a translucent, water-soluble, semisolid gel (autogel) has been shown to control GH hypersecretion for 4 weeks. This delivery system is not available in the United States.

The currently available somatostatin analogs are used in 3 ways: prior to surgery; as adjuvant therapy (either alone or combined with radiation therapy) after surgery; or, in some patients, as primary therapy. The rationale for use prior to surgery is suggested by data that show improved cure rates with perioperative somatostatin analog therapy, as well as increased control of acromegaly complications (eg, cardiovascular, respiratory, and metabolic) prior to surgery.[32] However, prospective data are lacking on the efficacy of these analogs in this setting.

As adjuvant therapy, several studies show good biochemical control with these analogs. Normalization of IGF-1 levels was achieved in 66% of patients treated with octreotide LAR[34-40] and 48% in those treated with lanreotide.[30,34,41-52]

As primary therapy, these analogs also show strong efficacy. Studies of primary octreotide (either short-acting or octreotide LAR) report normalization of GH levels in 43% to 79% of patients and normalization of IGF-1 levels in 50% to 68% of patients.[8,16,27-29] Studies of primary therapy with lanreotide report normalization of GH levels in 50% to 78% of patients and normalization of IGF-1 levels of 50% to 70%.[16,26,29,32,53]

Tumor shrinkage has not been assessed as a therapeutic outcome in all studies of somatostatin analogs, and studies that do make this assessment do not use a uniform definition of tumor reduction or the same methodology for measuring tumor size. Therefore, comparisons among studies are difficult. Recent critical reviews summarizing these studies conclude that somatostatin analog treatment achieves tumor shrinkage in a significant proportion of patients harboring GH-secreting pituitary adenomas.[54,55]

Tumor shrinkage has been assessed most frequently in studies of short-acting octreotide; overall, ~50% of patients receiving this treatment had tumor shrinkage. In 7 studies with octreotide LAR, 57% of patients overall had a decrease in tumor size; however, some patients were preselected for responsiveness to octreotide, which may have biased results.[54] Tumor shrinkage has been studied as an end point in 8 studies of treatment with lanreotide depot; overall, 24% of patients had a decrease in tumor size.[54] It should be noted, however, that one of these studies was too short to produce useful tumor-shrinkage data, and 2 of the studies evaluated lanreotide after a short washout period following octreotide therapy. Across all studies with all agents, patients receiving primary therapy experienced greater tumor shrinkage than those undergoing adjunctive therapy.

Somatostatin analogs are well tolerated, and their side effects seldom result in treatment discontinuation. Most adverse events are transient and occur during the first weeks of treatment and include gastrointestinal symptoms (nausea, bloating, and loose stools). Asymptomatic gallstones may be encountered in ~25% of patients during chronic therapy.[32,56,57]

Dopamine Agonists
Dopamine agonists inhibit GH secretion in some patients with acromegaly[32,58] and appear to have particular benefit in patients with adenomas that express both GH and prolactin (ie, acromegaly patients with hyperprolactinemia).[32,59]

A number of dopamine agonists are used as adjuvant medical therapy for acromegaly patients, including bromocriptine (which is indicated in US Food and Drug Administration [FDA] labeling for the treatment of acromegaly) and pergolide, lisuride, quinagolide, and cabergoline (which are not indicated in FDA labeling for the treatment of acromegaly). Although there are few data directly comparing the safety and efficacy of these agents in the treatment of acromegaly, studies do show the superior efficacy and tolerability of cabergoline compared with bromocriptine[60-64] and quinagolide[61,64] in treating hyperprolactinemia. A study of the efficacy of cabergoline reported normalization of IGF-1 levels in 35% of patients and GH suppression of < 2 mcg/L in 44% of patients, with some tumor shrinkage, particularly in tumors that secreted both GH and prolactin.[60] In particular, biochemical control was related to lower pretreatment IGF-1 levels (ie, < 750 mcg/L). In patients with resistant disease, the addition of cabergoline to somatostatin analog therapy may improve biochemical control.[65]

Compared with somatostatin analogs or the GH receptor antagonist, dopamine agonists are less effective in treating acromegaly. Limited indications for their use may be for patients with combined GH- and prolactin-secreting pituitary adenomas and in patients with lower pretreatment hormonal levels (ie, IGF-1 < 750 mcg/L).

GH Receptor Antagonists
Pegvisomant, a GH receptor antagonist, was designed to act on GH receptors to block GH action.[32,66] 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 signaling events.

Pegvisomant has shown strong efficacy, with over 90% of patients achieving normalization of IGF-1 levels.[1,11,19] Associated with this tight biochemical control is significant improvement in the signs and symptoms of acromegaly as well as correction of metabolic defects, such as insulin resistance.[10,67-69] The drug is administered once daily by subcutaneous injection.

Unknown, however, are the long-term effects of this agent on pituitary tumor growth. One study found no significant change in tumor volume in patients treated with pegvisomant over a mean of 1 year of follow-up,[11,66] whereas another found that tumors grew in some patients while on this therapy.[66,70] Further evaluation of safety is also needed, with elevations in liver enzymes reported in patients receiving pegvisomant.[35,66,71] Other limitations of this drug include the possibility of lowering IGF-1 levels into the range of those encountered in states of GH deficiency.

Pegvisomant administration achieves normal IGF-1 levels in most patients,[71,72] and current recommendations suggest the use of this agent in patients who fail or are intolerant to surgical or medial 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.[1]

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