title: Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly.
abstract: OBJECTIVE
  The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.
  
  
  METHODS
  To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands.
  
  
  METHODS
  β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients.
  
  
  RESULTS
  β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = -0.69, P = 0.0011 and ρ = -0.67, P = 0.0016).
  
  
  CONCLUSIONS
  Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Gatto
authors.affiliation: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nienke R
authors.initials: NR
authors.lastname: Biermasz
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands Pituitary Center RotterdamErasmus MC, Rotterdam, The Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.affiliation: PathologyErasmus MC, Rotterdam, The Netherlands Pituitary Center RotterdamErasmus MC, Rotterdam, The Netherlands.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Fadime
authors.initials: F
authors.lastname: Dogan
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands Pituitary Center RotterdamErasmus MC, Rotterdam, The Netherlands.
authors.forename: Aart-Jan
authors.initials: AJ
authors.lastname: van der Lely
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands Pituitary Center RotterdamErasmus MC, Rotterdam, The Netherlands.
authors.forename: Sebastian J C M M
authors.initials: SJ
authors.lastname: Neggers
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.affiliation: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pereira
authors.affiliation: EndocrinologyDepartment of Internal Medicine and Medical Specialties (DIMI) and Center of Excellence for Biomedical Research (CEBR), IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ferone
authors.affiliation: Department of Internal MedicineDivision Endocrinology, Erasmus MC, Rotterdam, The Netherlands Pituitary Center RotterdamErasmus MC, Rotterdam, The Netherlands l.hofland@erasmusmc.nl.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D000172:Acromegaly / Q000188:drug therapy* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D019390:Arrestins / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012189:Retrospective Studies; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D016896:Treatment Outcome; D055815:Young Adult; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; D019390:Arrestins; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D013004:Somatostatin; C094573:somatostatin receptor 5