Diagnosis and Management of Acromegaly in 2012
For somatostatin analog and dopamine agonist administration, serum GH and IGF-1 are the appropriate biochemical markers for following activity. Repeat testing is performed following dose changes at eight- to 12-week intervals.27
analog therapy, 36.6 % of patients had a significant (10 % to greater than 45 %) reduction in tumor size.53
GH suppression following glucose administration
may be useful for monitoring the efficacy of medical therapy,39–41 although a recent study questioned the use of this test in this setting.27 With administration of pegvisomant, serum IGF-1 only should be measured to monitor dose efficacy and GH levels should not be assessed. GH levels rise with pegvisomant administration and these GH levels have no impact on pegvisomant dosing.42,43
Dopamine Agonists
Bromocriptine and cabergoline are dopamine agonists that have been shown to be efficacious in the management of acromegaly. Both are orally administered and are less expensive than the other options, and therefore are often used as medical therapy. However, bromocriptine normalizes IGF-1 levels in approximately 8 % of patients and high doses are often required.44
Cabergoline, a more selective dopamine-2 receptor
agonist, may be effective in up to 40 % of subjects with doses of 1.0–1.75 mg/week, although doses of up to 7 mg weekly may be necessary.45,46
Subjects with modest elevation of their serum IGF-1 level may be the most responsive to dopamine agonist therapy. Some studies have suggested that co-secretion of prolactin may predict response, but this has not been supported by other studies.47,48
Adverse effects of both
bromocriptine and cabergoline include gastrointestinal upset, nasal congestion, fatigue, orthostasis, and headache, but cabergoline may be better tolerated than bromocriptine. When used in higher doses (e.g., greater than 3 mg daily) in patients with Parkinson’s disease, cabergoline has been associated with an increased risk of echocardiographic valvular abnormalities.49
There are no definitive data
that clearly link the use of cabergoline with cardiac valve disease in acromegaly, and the implication of this finding for patients with acromegaly remains unclear.
Somatostatin Analogs
Longer-acting depot preparations, including octreotide LAR (intramuscular) and lanreotide autogel (deep subcutaneous), are administered as monthly injections. In a meta-analysis, depot formulations resulted in approximately 55 % normalization of GH and 67 % normalization of IGF-I levels.51
similar pharmacologic and efficacy profiles.52
Octreotide LAR and lanreotide autogel have In cases where IGF-1 levels
fall excessively, somatostatin analogs may be administered at six-week intervals or longer. Somatostatin analog administration may result in tumor shrinkage. In one review of 14 studies using primary somatostatin
US ENDOCRINOLOGY
Somatostatin analogs are the mainstay of medical therapy for acromegaly and are highly effective at improving both biochemical parameters and medical comorbidities. There are two available somatostatin analog formulations: octreotide and lanreotide. Short-acting octreotide is administered at 0.05–0.3 mg subcutaneously up to three to four times a day. The advantages of short-acting octreotide include rapid action and a considerably smaller cost than the depot formulations. It is recommended that short-acting octreotide be administered for two weeks at a dosage of 0.1 mg three times daily prior to initiation of the octreotide LAR depot, to assess the response and tolerability of octreotide. However, this practice is not generally followed and, instead, one or two doses of short-acting subcutaneous octreotide may be administered to assess for significant toxicity.50
Pegvisomant
Pegvisomant is a recombinantly derived analog of human GH that acts as a highly selective GH receptor antagonist.42,43
Administration of
pegvisomant leads to a reduction in IGF-1 levels, with a rise in circulating GH levels. Therefore, serum IGF-I, and not GH, is used to monitor the biochemical response to therapy. In the pivotal study involving a double-blind, placebo-controlled 12-week trial, daily subcutaneous administration of pegvisomant normalized IGF-1 in 89 % of cases.42
In the
follow-up extension study involving 152 patients treated for up to 18 months, IGF-I normalized in 97 % of patients.43
Therefore,
pegvisomant is highly effacious, and it may be particularly useful in improving glucose homeostasis in patients with glucose intolerance or overt type 2 diabetes.56
use of weekly or twice-weekly formulations of pegvisomant, as less frequent administration may prove easier for patient use.57
Pegvisomant does not target the tumor, nor does it have tumor antiproliferative effects, giving rise to concern that its use may therefore lead to tumor growth. However, observational studies have shown tumor growth to be uncommon and, when present, it may reflect the presence of more aggressive tumors or rebound growth following recent discontinuation of a somatostatin analog.58
It is recommended that
patients undergo monitoring with serial MRI scans; for example, at six-month intervals during the first year and then annually. Pegvisomant therapy is associated with abnormalities in liver function tests; in the German Pegvisomant Observational Study, transaminase levels greater than three times normal were noted in 5.2 % of subjects.59
These
transaminase elevations are usually asymptomatic and often transient and self-limiting, despite continued administration of pegvisomant.59 Regular monitoring of liver function tests is recommended with discontinuation of the drug if these abnormalities are significantly elevated. Additional and uncommon adverse effects include an influenza-like illness, local allergic reactions, and local lipohypertrophy.60
How to Manage the Patient with Somatostatin Analog Resistance? There are several management options for patients who are resistant to somatostatin analogs. One option is to increase the somatostatin analog to a high-dose formulation (e.g., octreotide LAR 60 mg monthly), as this
123 More recently, there has been an increase in the
function of the somatostatin receptor subtype 2 density, although the presence of receptor subtypes is not routinely assessed.54
The efficacy of somatostatin analogs is a Response to
somatastatin analogs is inversely correlated with tumor size and degree of GH hypersecretion. The acute GH reduction following a single subcutaneous dose of octreotide and the degree of radiolabeled octreotide uptake have not been shown to be accurate in predicting biochemical remission.55
The most common adverse effects are abdominal cramping and diarrhea, which are usually noted within the first 72 hours after each depot injection. Chronic somatostatin analog use is also associated with an increased incidence of gallbladder sludge and gallstone formation, but these effects are not clinically significant in most patients.51
Less
frequently, hair loss, bradycardia, constipation, glucose intolerance, and diabetes are described.
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