Stine Lyngvi Fougner

Preoperative Octreotide Treatment in Newly Diagnosed Acromegalic Patients with Macroadenomas Increases Cure Short-Term Postoperative Rates: A Prospective, Randomized Trial

CONTEXT Surgery is the primary treatment of acromegaly. However, it often fails to cure the patient. New strategies that improve surgical outcome are needed. OBJECTIVE Our objective was to investigate whether 6-month preoperative treatment with octreotide improves the surgical outcome in newly diagnosed acromegalic patients. PATIENTS During a 5-yr period (1999-2004), all newly diagnosed acromegalic patients between 18 and 80 yr of age in Norway were screened and invited to participate in the study. A total of 62 patients was included in the Preoperative Octreotide Treatment of Acromegaly study. RESEARCH DESIGN AND METHODS After a baseline evaluation, patients were randomized directly to transsphenoidal surgery (n = 30) or pretreatment with octreotide (n = 32) 20 mg im every 28th day for 6 months before transsphenoidal surgery. Cure was evaluated 3 months postoperatively primarily by IGF-I levels. RESULTS According to the IGF-I criteria, 14 of 31 (45%) pretreated patients vs. seven of 30 (23%) patients with direct surgery were cured by surgery (P = 0.11). In patients with microadenomas (< or = 10 mm), one of five (20%) pretreated vs. three of five (60%) with direct surgery were cured (P = 0.52). In patients with macroadenomas, 13 of 26 (50%) pretreated vs. four of 25 (16%) with direct surgery were cured (P = 0.017). CONCLUSIONS Six-month preoperative octreotide treatment might improve surgical cure rate in newly diagnosed acromegalic patients with macroadenomas. These results have to be confirmed in future studies.

Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Context  Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas.

The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma

Objective  Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G‐protein α subunit (Gsα) mutation (gsp oncogene)‐positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide.

The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response.

CONTEXT Appropriate cell-to-cell adhesion is fundamental for the epithelial phenotype of pituitary cells. Loss of the adhesion protein E-cadherin has been associated with invasiveness, metastasis, and poor prognosis in cancers of epithelial origin. In somatotroph adenomas, a variable and reduced expression of E-cadherin has been demonstrated. In addition, nuclear translocation of E-cadherin was found to correlate with pituitary tumor invasion. OBJECTIVE The objective was to examine the protein expression of E-cadherin in somatotroph pituitary adenomas in relation to adenoma size, invasiveness, and somatostatin analog (SMS) efficacy. PATIENTS AND METHODS Eighty-three patients were included, and 29 were treated preoperatively with SMS. Adenoma E-cadherin protein expression was analyzed by Western blot (61 patients) and immunohistochemistry (IHC) (80 patients) with antibodies directed against both extracellular and intracellular domains (IHC). The acute (direct surgery group) and long-term (preoperatively treated group) SMS responses were evaluated. Baseline tumor volume and invasiveness were measured on magnetic resonance imaging scans. RESULTS Membranous E-cadherin was lost in several adenomas. Nine of these were nuclear E-cadherin positive. The E-cadherin protein expression correlated negatively to tumor size and positively to acute SMS response. Low E-cadherin levels (preoperatively treated group only) and loss of membranous E-cadherin correlated to tumor invasiveness. The E-cadherin level correlated positively to tumor reduction after SMS treatment, and adenomas with nuclear E-cadherin staining had lower IGF-I reduction and tumor shrinkage. Preoperatively treated adenomas had reduced E-cadherin protein levels, but the IHC expression was unaltered. CONCLUSION Reduced E-cadherin expression may correlate to a dedifferentiated phenotype in the somatotroph pituitary adenomas.

Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly

Background  Primary, preoperative medical treatment is an option in selected patients with acromegaly, but a subset of patients respond poorly. Valid prediction of response to somatostatin analogues (SA) might thus alter treatment stratification. The aims of this study were to assess whether T2 signal intensity could determine long‐term response to first‐line SA treatment and to assess clinical and biochemical baseline characteristics, as well as histological subtype in relation to the magnetic resonance imaging (MRI) appearances.

Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure.

Objective  Treatment with somatostatin analogues is the primary medical treatment of acromegaly. Controversies still exist whether acute octreotide effect predicts long‐term biochemical effects, tumour regression or surgical cure. This prospective study investigates effect of 6‐month treatment with octreotide long‐acting repeatable (LAR) on insulin‐like growth factor‐1 (IGF‐1) and growth hormone (GH) levels, pituitary function, tumour regression and postoperative cure in de novo acromegalic patients.

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial

OBJECTIVE Randomised studies have demonstrated a beneficial effect of pre-surgical treatment with somatostatin analogues (SSA) in acromegaly when evaluated early postoperatively. The objective of this study was to evaluate the long-term surgical cure rates. METHODS Newly diagnosed patients were randomised to direct surgery (n=30) or 6-month pretreatment with octreotide LAR (n=32). The patients were evaluated 1 and 5 years postoperatively. Cure was defined as normal IGF1 levels and by normal IGF1 level combined with nadir GH <2 mU/l in an oral glucose tolerance test, all without additional post-operative treatment. A meta-analysis using the other published randomised study with long-term analyses on preoperative SSA treatment was performed. RESULTS The proportion of patients receiving post-operative acromegaly treatment was equal in the two groups. When using the combined criteria for cure, 10/26 (38%) macroadenomas were cured in the pretreatment group compared with 6/25 (24%) in the direct surgery group 1 year postoperatively (P=0.27), and 9/22 (41%) vs 6/22 (27%) macroadenomas, respectively, 5 years postoperatively (P=0.34). In the meta-analysis, 16/45 (36%) macroadenomas were cured using combined criteria in the pretreatment group vs 8/45 (18%) in the direct surgery group after 6-12 months (P=0.06), and 15/41 (37%) vs 8/42 (19%), respectively, in the long-term (P=0.08). CONCLUSION This study does not prove a beneficial effect of SSA pre-surgical treatment, but in the meta-analysis a trend towards significance can be claimed. A potential favourable, clinically relevant response cannot be excluded.

Low Levels of Raf Kinase Inhibitory Protein in Growth Hormone-Secreting Pituitary Adenomas Correlate with Poor Response to Octreotide Treatment

CONTEXT Excessive GH production by pituitary tumors causes acromegaly. Medical treatment of acromegaly with somatostatin analogs (SMSs), like octreotide, is well established, but the clinical effect is variable. One mechanism for octreotide effect is inhibition of the MAPK signaling pathway after binding to the G protein-coupled somatostatin receptor. Nonphosphorylated Raf kinase inhibitory protein (RKIP) binds to and inhibits Raf1 kinase, and thereby attenuates MAPK signaling, whereas phosphorylated RKIP inhibits G protein receptor internalization and degradation due to inhibition of G protein receptor kinase 2. OBJECTIVE Our objective was to study RKIP levels in pituitary somatotroph adenomas, and relate them to clinical characteristics and response to octreotide treatment in patients with acromegaly. PATIENTS AND METHODS RKIP level was analyzed by Western blot of proteins extracted from somatotroph tumors frozen a short time after surgery in 51 patients with active acromegaly. An acute somatostatin test was performed in 46 of the patients, and in 21 the IGF-I level before and 6 months after SMS treatment was available. RESULTS The adenoma RKIP level correlated significantly to both the acute and the long-term octreotide responses on serum levels of GH and IGF-I, respectively. In multiple regression analyses, the RKIP level was a significant determinant for both the GH reduction in the acute test and the IGF-I reduction after approximately 6 months. CONCLUSION The RKIP level in somatotroph adenomas seems to be important for the clinical effect of SMS treatment, in which low levels of RKIP correlate to poor clinical response to SMSs.

Associations between Body Composition, Circulating Interleukin-1 Receptor Antagonist, Osteocalcin, and Insulin Metabolism in Active Acromegaly

OBJECTIVE Patients with active acromegaly display a range of abnormalities in glucose metabolism. To elucidate interactions between bone and energy homeostasis in relation to excess GH, we sought to determine whether these patients were characterized by alterations in circulating levels of adipokines and cytokines and potential interactions with osteocalcin (OCN) and insulin resistance. METHODS Forty-seven patients with active acromegaly: 26 women and 21 men (49 +/- 11, mean +/- sd) were evaluated and compared with age-, sex-, and body mass index-matched controls by x-ray absorptiometry, biochemical analysis [GH, IGF-I, OCN, leptin, adiponectin, retinol binding protein 4, IL-6, IL-1beta, and IL-1 receptor antagonist (IL-1Ra)], and glucose metabolism (homeostasis model assessment). In vitro effects of GH/IGF-I on IL-1beta/IL-1Ra in THP-1 macrophages and human white adipocytes as well as effects of GH/IGF-I in combination with carboxylated and undercarboxylated OCN on glucose-stimulated insulin release in human pancreatic islets were also investigated. RESULTS Patients with acromegaly were characterized by markedly decreased serum levels of IL-1Ra and increased IL-1beta and IL-1beta to IL-1Ra ratio, suggesting enhanced IL-1 activity. The decreased IL-1Ra was strongly associated with increased OCN levels in multivariate models and was significantly correlated with decreased total body fat mass. In macrophages, IGF-I/GH significantly decreased the release of IL-1Ra and increased IL-1beta, suggesting that the decreased circulating IL-1Ra levels in acromegaly could reflect both direct and indirect mechanisms. Finally, circulating OCN was the main determinant of insulin resistance and beta-cell function in acromegaly and in vitro, a blunted insulin response was observed in the presence of OCN and GH/IGF-I. CONCLUSION These data confirm and establish novel and complex interactions between bone, energy metabolism, and adipose tissue and suggest an unfavorable effect of OCN and GH/IGF-I in combination on insulin metabolism in active acromegaly.

Gene expression profiling identifies ESRP1 as a potential regulator of epithelial mesenchymal transition in somatotroph adenomas from a large cohort of patients with acromegaly.

CONTEXT The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking. OBJECTIVE We hypothesized that characterization of EMT-related transcripts in somatotroph adenomas could identify novel therapeutic targets in individuals with poor response to SA treatment and provide more knowledge of the mechanism of EMT progression. PATIENTS Fifty-three patients with acromegaly participated in the study. RESEARCH DESIGN AND METHODS We performed microarray analysis of 16 adenomas, eight with high expression and eight with low expression of E-cadherin, in order to identify EMT-related transcripts. Candidate transcripts were further explored in vivo in 53 adenomas and in vitro in a rat pituitary GH-producing cell (GH3) after exploring three models for reducing E-cadherin and inducing a mesenchymal phenotype. RESULTS In vivo E-cadherin mRNA expression in tumor tissue is associated negatively with tumor size and invasiveness and positively with GH and IGF-I levels in serum and response to SA treatment. Microarray and subsequent PCR analysis identify several EMT-related genes associated with E-cadherin expression. In vitro, few of these EMT-related genes were regulated by silencing E-cadherin or by TGF-β1 treatment in GH3 cells. In contrast, silencing Esrp1 in GH3 cells regulated many of the EMT-related transcripts. CONCLUSION These results indicate that ESRP1 could be a master regulator of the EMT process in pituitary adenomas causing acromegaly.