title: 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.
  
  
  METHODS
  Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) 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 (P=0.859). 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 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, 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.
authors.affiliation: Department of Internal MedicineEndocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The NetherlandsDepartment of Internal MedicineEndocrinology Section, Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark s.franck@erasmusmc.nl.
authors.forename: S E
authors.initials: SE
authors.lastname: Franck
authors.affiliation: Department of Internal MedicineEndocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The NetherlandsDepartment of Internal MedicineEndocrinology Section, Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Lely
authors.affiliation: Department of Internal MedicineEndocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The NetherlandsDepartment of Internal MedicineEndocrinology Section, Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: P J D
authors.initials: PJ
authors.lastname: Delhanty
authors.affiliation: Department of Internal MedicineEndocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The NetherlandsDepartment of Internal MedicineEndocrinology Section, Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: J O L
authors.initials: JO
authors.lastname: Jørgensen
authors.affiliation: Department of Internal MedicineEndocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The NetherlandsDepartment of Internal MedicineEndocrinology Section, Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: S J C M M
authors.initials: SJ
authors.lastname: Neggers
mesh_terms: D000172:Acromegaly / Q000188:drug therapy*; D000236:Adenoma / Q000188:drug therapy*; D000328:Adult; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D005091:Exons; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D008565:Membrane Proteins; C405010:delta-hGHR; D019382:Human Growth Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; C406545:pegvisomant