Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

Abstract

Background: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. Objective: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. Design: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (O1.2 upper limit of normal; nZ112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. Results: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (PZ0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (PZ0.337) or PEGV serum levels (PZ0.433) was observed between the two groups. However, adenoma size decreased significantly (O20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (PZ0.034, OR: 4.6 (CI: 1.1-18.9)). Conclusions: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size. IntroductionDisease activity and phenotype is diverse among patients with acromegaly. Comorbidities such as hypertension, cardiomyopathy, type 2 diabetes, sleep apnea and osteoarthritis are influenced by the severity and the duration of growth hormone (GH) hypersecretion (1). Pegvisomant (PEGV) is a competitive GH receptor (GHR) antagonist that is used in the treatment of acromegaly (2). The required dose of PEGV to achieve disease control as assessed by the normalization of insulin-like growth factor 1 (IGF1) levels differs significantly between individual patients (2). Baseline IGF1 appears to be a predictor for the required dose (3). Other factors known to influence the required dose are sex, body weight and previous radiotherapy (4). However, GHR polymorphisms seem to have an influence as well (5, 6). A polymorphism of the GHR that lacks exon 3 (d3-GHR) during splicing is common in the general population. About half of the population is homozygous for the full-length GHR (fl-GHR), 30-40% is heterozygous for d3-GHR and 10-20% is homozygous for this deletion (7,8,9). It has been reported that the d3-GHR polymorphism shows a comparable distribution between different cohorts of acromegalic patients (6,10,11,12). Multiple studies show that the fl-GHR and d3-GHR have co...

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

“…Two studies, indeed, reported a lower required PEGV dose during disease control in acromegaly patients with the d3-GHR genotype [16,24] . However, more recent studies in larger acromegaly cohorts could not confirm these findings [25,26] . These contradictory reports on the influence of d3-GHR in acromegaly patients regarding PEGV treatment responses and the PEGV doses required to normalize IGF-I levels motivated us to conduct a systematic review of the literature to identify studies examining this question and to perform a meta-analysis.…”

“…One original study [16] was excluded as the majority of the patients were included in a larger more recent study, which was already part of this metaanalysis [25] . Finally, we included 3 published original studies and 1 conference abstract describing one relevant acromegaly cohort [24][25][26]29] . All 4 selected papers included data of both requested outcomes: (1) lowest IGF-I level expressed as ULN during PEGV treatment and (2) the required PEGV dose to achieve the lowest IGF-I level.…”

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

“…Additionally, some studies evaluated the GHR polymorphisms as a possible cause of a lower response to the drug, with conflicting results regarding whether patients who present the exon-3 deleted GHR (d3GHR) had a better response to pegvisomant (25)(26)(27)(28).…”

MANAGEMENT OF ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly

“…However, more recently, a large multicenter study (111 patients) and a study from our group did not find a difference in the response rates to pegvisomant treatment between patients with the d3GHR and those with the flGHR 31,104 . Additionally, another study described no difference in the response rates to combination therapy with pegvisomant and fg-SRL in patients with the different isoforms of GHR 105 . Therefore, current knowledge suggests that d3GHR is not a biomarker of response to pegvisomant.…”