Ansgar Heck

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.

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.

Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide

CONTEXT Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. OBJECTIVE We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. DESIGN, SETTING, PATIENTS The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. INTERVENTION Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). MAIN OUTCOME MEASURE SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. RESULTS The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. CONCLUSION Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.

Effects of Parathyroidectomy Versus Observation on the Development of Vertebral Fractures in Mild Primary Hyperparathyroidism

CONTEXT Mild primary hyperparathyroidism (PHPT) is a common disease especially in middle-aged and elderly women. The diagnosis is frequently made incidentally and treatment strategies are widely discussed. OBJECTIVE To study the effect of parathyroidectomy (PTX) compared with observation (OBS) on biochemistry, safety, bone mineral density (BMD), and new fractures. DESIGN Prospective, randomized controlled study (SIPH study), with a 5-year follow-up. SETTING The study was conducted at multicenter, tertiary referral centers. PATIENTS Of 191 randomized patients with mild PHPT, biochemical data were available for 145 patients after 5 years, with a mean age at inclusion of 62.8 years (OBS group, 9 males) and 62.1 years (PTX group, 10 males). INTERVENTION Parathyroidectomy vs observation. MAIN OUTCOME MEASURES Biochemistry, BMD, and new radiographic vertebral fractures. RESULTS Serum-calcium and PTH-levels normalized after surgery and did not deteriorate by observation. BMD Z-scores were normal at inclusion in the lumbar spine (LS) and femoral neck (FN). For LS, BMD Z-scores were stable for 5 years with observation, but decreased in FN (P < .02). After surgery, BMD Z-scores increased significantly in both compartments (P < .02 for both), with a highly significant treatment effect of surgery compared to observation (P < .001). During follow-up, five new clinically unrecognized vertebral fractures were found in 5 females, all in the OBS group (P = .058). CONCLUSION Even though new vertebral fractures occurred only in the observation group, the frequency was not significantly different from the surgery group. Longer follow-up is needed before firm conclusions can be drawn about the long-term safety of observation, as opposed to surgery.

Insulin sensitivity, body composition and adipose depots following 12 w combined endurance and strength training in dysglycemic and normoglycemic sedentary men

Abstract Context: Insulin resistance and dysglycemia are associated with physical inactivity and adiposity, and may be improved by exercise. Objective: Investigate the effect of exercise on insulin sensitivity, body composition and adipose depots in sedentary men with (n = 11) or without (n = 11) overweight and dysglycemia. Material and methods: Euglycemic-hyperinsulinemic clamp, ankle-to-neck MRI, MRS, muscle and adipose tissue biopsies before and after 12 weeks combined strength and endurance exercise. Results: Insulin sensitivity, VO2max, strength, whole-body and muscle fat content, and abdominal adipose depots were improved without obvious differences between normo- and dysglycemic men. Hepatic fat, waist circumference and subcutaneous adipose tissue were reduced in the dysglycemic group. For both groups plasma adiponectin was reduced, whereas IL-6 was unchanged. Visceral fat was preferentially lost compared with other adipose depots. Discussion and conclusion: Body composition, fat distribution and insulin sensitivity improved following training in sedentary middle-aged men with and without dysglycemia.

Attenuated RORC expression in the presence of EMT progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery.

Somatostatin analogs (SA) have been established as the first line medical treatment for acromegaly, but following long-term treatment, SA normalizes GH and IGF-I levels in only 40–60% of patients. The epithelial marker E-cadherin plays a crucial role in the epithelial mesenchymal transition (EMT) and is associated with a poor response to SA treatment. We hypothesized that the characterization of transcripts regulated by SA in somatotroph adenomas with high and low E-cadherin expression may identify signaling pathways and mediators that can explain the poor response to SA treatment. We performed a microarray analysis of sixteen adenomas with different levels of E-cadherin and SA treatment to identify regulated transcripts. Candidate transcripts were further explored in vivo in sixty-five adenomas, and interactions between SA treatment and EMT progression on mRNA expression profiles and associations with clinical recovery were assessed. Finally, the effects of SA treatment on adenoma cells in vitro from acromegalic patients were determined. Microarray analysis of selected adenomas with differential E-cadherin expression, as a marker of EMT progression, identified 172 genes that displayed differential expression that was dependent on SA treatment. The validation of selected candidates in the entire cohort identified 9 transcripts that showed an interaction between E-cadherin expression and SA treatment. Further analysis of the impact of these genes suggests that attenuated RORC expression in somatotroph adenomas is associated with increased tumor size and a blunted clinical response. Our study indicates that attenuated RORC may be involved in the poor clinical response to SA treatment in patients with acromegaly.

The Metabolic Risk in Patients Newly Diagnosed with Acromegaly Is Related to Fat Distribution and Circulating Adipokines and Improves after Treatment

Background/Aims: Adipose tissue (AT) distribution is closely related to metabolic disease risk. Growth hormone (GH) reduces visceral and total body fat mass and induces whole-body insulin resistance. Our aim was to assess the effects of total and visceral AT (VAT) distribution and derived adipokines on systemic insulin resistance and lipid metabolism in acromegaly. Methods: Seventy adult patients with active acromegaly (43 males, age 49 ± 14 years) were evaluated before treatment, and a subset (n = 30, 20 males) was evaluated after treatment for acromegaly. Body composition and VAT, glucose metabolism parameters, lipids, C-reactive protein, and selected adipokines (vaspin, omentin, adiponectin, and leptin) were measured. Results: At baseline, VAT was positively associated with glucose metabolism parameters and with lipids. GH, but not IGF-I, was negatively associated with all AT depots (visceral, trunk, limbs, and total; 0.41 ≤ r ≤ 0.61, p < 0.001 for all) and positively associated with vaspin (r = 0.31, p = 0.013). The fat deposition after treatment was predominantly located on trunk and visceral depots. The lipid profile partially improved, with increases in HDL and apolipoprotein A-I and a decrease in lipoprotein(a). Vaspin decreased and omentin increased. Adiponectin and leptin did not change significantly. The improvement in homeostasis model assessment for insulin resistance (HOMA-IR) was best predicted by the decreases in IGF-I and vaspin and the lack of an increase in trunk fat (R2 = 0.59, p = 0.001). Conclusions: (1) VAT is a metabolic risk factor for patients with active acromegaly; (2) vaspin and omentin levels are influenced by the disease activity but are not associated with VAT mass; (3) fat deposition after treatment occurs predominantly on the trunk and in visceral depots, and (4) insulin resistance decreases and the lipid profile partially improves with treatment.

Effect of surgery vs observation: skeletal 5-year outcomes in a randomized trial of patients with primary HPT (the SIPH study)†

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long‐term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm2 and T‐scores and on biochemical markers of bone turnover (P1NP and CTX‐1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow‐up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX‐1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm2) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm2) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long‐term observation in patients with mild PHPT.

MRI T2 characteristics in somatotroph adenomas following somatostatin analog treatment in acromegaly

MRI T2 characteristics in somatotroph adenomas following somatostatin analogue treatment in acromegaly

Epithelial Splicing Regulator Protein 1 and Alternative Splicing in Somatotroph Adenomas

Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.