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Pituary Disorders


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


this setting.27 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 normalises 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 Analogues


Somatostatin analogues are the mainstay of medical therapy for acromegaly and are highly effective at improving both biochemical parameters and medical co-morbidities. There are two available somatostatin analogue 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


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 % normalisation of GH and 67 % normalisation of IGF-I levels.51 Octreotide LAR and lanreotide autogel have similar pharmacological and efficacy profiles.52


The most common adverse effects are abdominal cramping and diarrhoea, which are usually noted within the first 72 hours after each depot injection. Chronic somatostatin analogue 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.


Pegvisomant


Pegvisomant is a recombinantly derived analogue 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 a pivotal study involving a double-blind, placebo-controlled 12-week trial, daily subcutaneous administration of pegvisomant normalised IGF-1 in 89 % of cases.42


In the follow-up extension study involving 152 patients


treated for up to 18 months, IGF-I normalised 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


More recently, there has been


an increase in the 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 tumour, nor does it have tumour antiproliferative effects, giving rise to concern that its use may therefore lead to tumour growth. However, observational studies have shown tumour growth to be uncommon and, when present, it may reflect the presence of more aggressive tumours or rebound growth following recent discontinuation of a somatostatin analogue.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


In cases where IGF-1 levels fall excessively,


somatostatin analogues may be administered at six-week intervals or longer. Somatostatin analogue administration may result in tumour shrinkage. In one review of 14 studies using primary somatostatin analogue therapy, 36.6 % of patients had a significant (10 % to greater than 45 %) reduction in tumour size.53


The efficacy of


somatostatin analogues is a function of the somatostatin receptor subtype 2 density, although the presence of receptor subtypes is not routinely assessed.54


Response to somatastatin analogues is 50


How to Manage the Patient with Somatostatin Analogue Resistance?


There are several management options for patients who are resistant to somatostatin analogues. One option is to increase the somatostatin analogue to a high-dose formulation (e.g., octreotide LAR 60 mg monthly), as this regimen may improve biochemical remission rates in an additional one-third of subjects.61


In a patient


with partial somatostatin analogue resistance, either pegvisomant or cabergoline could be added to the somatostatin analogue for additive effect. For example, the addition of pegvisomant to a


EUROPEAN ENDOCRINOLOGY


inversely correlated with tumour size and degree of GH hypersecretion. The acute GH reduction following a single subcutaneous dose of octreotide and the degree of radiolabelled octreotide uptake have not been shown to be accurate in predicting biochemical remission.55


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