The Effect of the Exon-3-Deleted Growth Hormone Receptor on Pegvisomant-Treated Acromegaly: A Systematic Review and Meta-Analysis

Abstract

Background: The common exon 3 deletion polymorphism of the growth hormone receptor (d3-GHR) is associated with disease severity in acromegaly patients. The GHR antagonist pegvisomant (PEGV) is highly effective in treating severe acromegaly. Response to PEGV treatment seems to be influenced by d3-GHR and appears to be more responsive to PEGV, although available results remain conflicting. Objective: To assess the influence of d3-GHR on the responsiveness of acromegaly patients to PEGV by compiling the evidence derived from the largest available studies. Design: A systematic review of the literature identified three published studies and one conference abstract. Acromegaly patients (n = 324, 49.7% d3-GHR carriers) were treated with either PEGV monotherapy or PEGV combined with long-acting somatostatin analogues and/or cabergoline. A meta-analysis of raw data from these studies was performed. Results: No significant effect of the d3-GHR was observed while bringing insulin-like growth factor I (IGF-I) levels below the upper limit of normal with PEGV, which was defined as the lowest IGF-I level during PEGV treatment (mean difference: -2.3%; 95% CI: -6.5 to 1.8, p = 0.270). The PEGV dose required to achieve the lowest IGF-I levels was also not significantly influenced by individuals carrying d3-GHR (mean difference: 4.1 mg weekly; 95% CI: -5.1 to 13.2, p = 0.385). For both outcomes, separate analysis of PEGV monotherapy and combination treatment gave similar results. Conclusion: Our findings suggest that the d3-GHR polymorphism has no effect on biochemical disease control in acromegaly, as it is not of added value for either the prediction of PEGV responsiveness or the determination of the required PEGV dose.

Pegvisomant and Pasireotide LAR as second line therapy in acromegaly: clinical effectiveness and predictors of response

“…The increased intracellular signal transduction may increase the sensitivity to GH: GH-deficient children carried the d3-GHR have an increased growth velocity and a higher final height (44) when treated with recombinant human GH (rhGH). In adult GHD patients, d3-GHR influences positively also metabolic and bone effects of rhGH (17,45). On the other hand, d3-GHR polymorphism confers higher susceptibility to GH stimulation in patients with acromegaly and may negatively affect phenotypic presentation and long-term complications of the disease, as showed in bone metabolism (46).…”

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues

“…Two studies previously reported about a GH receptor polymorphism lacking exon 3, which seemed to have an influence as well during PEGV dosing (21,22). However, more recent studies in larger acromegaly cohorts clearly state that this polymorphism has a clinical effect on neither the PEGV response nor the determination of the required PEGV dose (23,24,25).…”

Novel therapies for acromegaly

“…For pegvisomant, some predictors have been described like pre-treatment GH and IGF-I levels, age and BMI ( 67 ). Expression of exon3-deleted growth receptor has been proposed as a predictor of response to pegvisomant in some studies, although it has not been confirmed in larger series ( 68 , 69 ).…”