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  • 1
    In: Endocrinology, The Endocrine Society, Vol. 154, No. 9 ( 2013-09-01), p. 3331-3343
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2013
    detail.hit.zdb_id: 2011695-0
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  • 2
    Online Resource
    Online Resource
    The Endocrine Society ; 2023
    In:  Journal of the Endocrine Society Vol. 7, No. Supplement_1 ( 2023-10-05)
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. Supplement_1 ( 2023-10-05)
    Abstract: Disclosure: C.M. Falch: Speaker; Self; Pfizer, Inc. K. Godang: None. T. Lekva: None. A. Heck: Speaker; Self; Ipsen, Recordati. J. Bollerslev: Advisory Board Member; Self; Pfizer, Inc. Speaker; Self; Ipsen, Pfizer, Inc. N.C. Olarescu: Speaker; Self; Pfizer, Inc., CORE2ED. Objective: Patients with active acromegaly present a decreased adipose tissue (AT) mass, and short-term studies show that the AT increases following treatment. However, it remains unclear if the increase is persistent in the long-term perspective. Aim: To characterize the depot specific changes of AT after treatment of acromegaly and identify contributing factors. Methods: In a clinically well-defined cohort of patients with acromegaly (n = 62), visceral (VAT), subcutaneous (SAT), total (TAT) adipose tissue, and android to gynoid ratio (A/G ratio) were measured by Dual Energy X-ray Absorptiometry (DXA). Measurements were assessed at diagnosis, and at a short- and long-term visit (median follow-up time (IQR): 1.9 (1.5-2.3) and 5.5 (3.6-9.6) years, respectively). Growth hormone (GH), insulin-like growth factor I (IGF-I), glucose and HbA1c levels, gonadal status, and the presence of diabetes mellitus were recorded prospectively. Remission status was assessed at the long-term visit (IGF-I ≤ 1.3 x ULN). Comparison between time points was performed using paired t-test or Mann-Whitney U test depending on distribution, and chi-square test for categorical variables. Differences in the temporal course were evaluated by mixed model analyses, adjusted for age. Results: VAT and A/G ratio increased at both time points, whereas SAT and TAT mainly increased at short-term, plateauing afterwards (p & lt; 0.05 for all). VAT and A/G ratio were higher in men (p = 0.035 and p & lt; 0.001), and the A/G ratio increased more compared to women (p = 0.003). BMI remained stable. Glucose and HbA1c decreased at short-term (p & lt; 0.05) and remained stable at long-term, with no obvious sex differences. The gonadal status had no effect on the increase in AT in women. The increase in VAT (p = 0.046), but not SAT, TAT or A/G ratio, was more pronounced in patients with diabetes mellitus. The increase in AT strongly correlated with the decrease in GH (SAT (R = -0.48), TAT (R = -0.51), p & lt; 0.001 for both) and IGF-I (VAT (R = -0.28, p = 0.036), SAT (R = -0.27, p = 0.046), TAT (R = -0.26, p = 0.048) at long-term. The decrease in glucose correlated with the decrease in HbA1c (R = 0.38, p = 0.009) and IGF-I (R = 0.32, p = 0.014) at long-term. Remission status had no effect on changes in AT mass during follow-up. Conclusion: Treatment of acromegaly leads to an increase in AT mass in a depot and sex specific manner both at short-term and long-term follow-up. Glucose metabolism improves rapidly after disease control and persists, whereas patients with diabetes mellitus have a higher VAT increase that may worsen their long-term metabolic outcome. Presentation: Thursday, June 15, 2023
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2881023-5
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  • 3
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 98, No. 11 ( 2013-11-01), p. E1730-E1739
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2013
    detail.hit.zdb_id: 2026217-6
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  • 4
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 100, No. 4 ( 2015-04), p. 1359-1367
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2015
    detail.hit.zdb_id: 2026217-6
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