Growth Hormone Receptor Variants and Response to Pegvisomant in Monotherapy or in Combination with Somatostatin Analogs in Acromegalic Patients: A Multicenter Study

Filopanti, Marcello; Olgiati, Luca; Mantovani, Giovanna; Corbetta, Sabrina; Arosio, Maura; Gasco, Valentina; Marinis, Laura De; Martini, Chiara; Bogazzi, Fausto; Cannavò, Salvatore; Colao, Annamaria; Ferone, Diego; Arnaldi, Giorgio; Pigliaru, Francesco; Peri, Alessandro; Angeletti, G; Jaffrain-Rea, Marie Lise; Lania, Andrea; Spada, Anna

doi:10.1210/jc.2011-1769

Cited by 40 publications

(36 citation statements)

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“…However, Filopanti and cols. (27) in a larger multicenter study (111 patients) did not find a difference in the response rates to pegvisomant treatment between those patients presenting d3GHR or the flGHR. Additionally, Franck and cols.…”

Section: Discussionmentioning

confidence: 71%

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

Kasuki

Machado

Ogino

et al. 2016

Arch. Endocrinol. Metab.

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Objective: To describe the safety and efficacy of pegvisomant therapy and the predictors of treatment response in acromegaly patients at a single tertiary reference center in Brazil. Materials and methods: We retrospectively reviewed the clinical, hormonal and radiological data of acromegaly patients treated with pegvisomant in our center. We also evaluated the presence of the d3 isoform of the growth hormone receptor (d3GHR). Results: Twenty-seven patients were included (17 women). Pegvisomant was used in combination with octreotide LAR in 20 patients (74%), in combination with cabergoline in one (4%) and as monotherapy in six (22%). IGF-I normalization was achieved in 23 patients (85%). Mild and transitory elevation of liver enzymes was observed in two patients (7.4%), tumor growth in one (3.4%) and lipodystrophy in two (7.4%). One patient stopped the drug due to headaches. The GHR isoforms were evaluated in 14 patients, and the presence of at least one d3GHR allele was observed in 43% of them, but it was not a predictor of treatment response. Only pretreatment IGF-I level was a predictor of treatment response. Conclusion: Pegvisomant treatment was highly effective and safe in our series of Brazilian patients. A better chance of disease control can be expected in those with lower pre-pegvisomant IGF-I levels. Arch Endocrinol Metab. 2016;60(5):479-85

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Section: Discussionmentioning

confidence: 71%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Kasuki

Machado

Ogino

et al. 2016

Arch. Endocrinol. Metab.

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“…To date, findings from 17 studies, which are summarized in Table 4, have not been consistent and the importance of the d3-GHR polymorphism in acromegaly management remains highly controversial (55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71). The number of patients with acromegaly examined varied from 19 to 186 among the reported series, with the prevalence of heterozygous d3/fl-GHR ranging from 13.3% to 57% and of d3-GHR homozygous from 0% to 22%.…”

Section: Ghr Polymorphism In Acromegalymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

Boguszewski

Barbosa

Svensson

et al. 2017

European Journal of Endocrinology

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Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized. The growth hormone receptor (GHR)Growth hormone (GH) exerts its biological effects by binding to the GH receptor (GHR). The GHR protein is positioned at the cell membrane of almost every cell in the human body and contains a 246 amino acids long extracellular (GH-binding) domain, a transmembrane domain and a 350 amino acids long intracellular (cytoplasmic) domain. In total, the GHR protein is composed of 638 residues (1). Binding of GH to the GHR induces a series of subtle conformational events within a receptor homodimer, rather than a simple receptor dimerization, promoting a realignment of the two receptors both by relative rotation and by closer apposition just above the cell membrane (2). The parallel receptor transmembrane domains are converted into a rotated crossover orientation and the lower parts of the transmembrane helices are separated. GHR activation

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“…Indeed, two studies reported that the required PEGV dose for normalization of IGF1 levels was significantly lower in acromegaly patients with a d3-GHR genotype (5,6). A later study, however, did not observe a better response of d3-GHR carriers during monotherapy PEGV nor during combination treatment with PEGV and somatostatin analogues (10). These inconsistent findings indicate that larger cohorts of acromegaly patients are needed to investigate whether the response to PEGV differs between d3-GHR and fl-GHR genotypes.…”

Section: Introductionmentioning

confidence: 98%

“…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 comparable binding properties, and that internalization of fl-GHR is as effective as d3-GHR (13,14,15).…”

Section: Introductionmentioning

confidence: 99%

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

Franck

Lely

Delhanty

et al. 2015

European Journal of Endocrinology

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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...

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Growth Hormone Receptor Variants and Response to Pegvisomant in Monotherapy or in Combination with Somatostatin Analogs in Acromegalic Patients: A Multicenter Study

Abstract: This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

Cited by 40 publications

References 28 publications

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

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

MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

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

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