scholarly journals Influence of pegvisomant on serum ghrelin and leptin levels in acromegalic patients

2010 ◽  
Vol 163 (5) ◽  
pp. 727-734 ◽  
Author(s):  
J Roemmler ◽  
B Otto ◽  
A M Arafat ◽  
M Bidlingmaier ◽  
J Schopohl
Keyword(s):  
Feedback Loop ◽  
De Novo ◽  
Inactive Disease ◽  
Strong Impact ◽  
Gh Receptor ◽  
Gh Receptor Antagonist ◽  
Total Ghrelin ◽  
Peg Treatment ◽  
L 96 ◽  
Serum Ghrelin

IntroductionPegvisomant (peg) is a GH receptor antagonist. In de novo acromegalic patients with high GH levels, ghrelin and leptin levels are reduced, suggesting a direct GH-mediated effect. The aim of our study was to evaluate whether peg treatment in acromegalic patients may abolish the GH impact on ghrelin and leptin levels.MethodsGhrelin, leptin and endogenous GH were measured in ten peg-treated acromegalic patients (three females/seven males, 47 years (28–57)), ten patients with active (act) and ten patients with inactive disease (inact) as well as in ten gender-, age- and body mass index (BMI)-matched healthy volunteers (controls). Endogenous GH was measured using a special in-house assay without interference by peg; total ghrelin and leptin were determined using a commercial RIA and an immunofluorometric in-house assay respectively.ResultsAge and BMI did not differ significantly between groups. Endogenous GH was significantly higher in peg (6.3 μg/l (1.5–41)) and act (9.3 μg/l (1.7–70)) compared with controls (0.1 μg/l (0.1–3.1)) and inact (0.35 μg/l (0.1–2.0), P<0.001). Ghrelin was significantly higher in peg (232 ng/l (96–351)) compared with act (102 ng/l (33–232), P<0.01), whereas ghrelin was not significantly different between the other groups. Leptin was highest in controls (19 μg/l (4–57)) and lowest in act (6 μg/l (2–21)), but this difference did not reach significance.ConclusionTreatment with peg seems to disrupt the feedback loop of ghrelin and GH, leading to elevated ghrelin levels. Furthermore, peg therapy appears not to have a strong impact on leptin levels, as acromegalic patients with and without peg treatment showed similar leptin levels.

scholarly journals Extra-hepatic Acromegaly

2013 ◽  
Vol 09 (01) ◽  
pp. 66
Author(s):  
Sanne E Franck ◽  
Aart Jan van der Lely ◽  
Sebastian Neggers ◽  
◽  
◽  
...  
Keyword(s):  
Growth Hormone ◽  
Serum Insulin ◽  
Somatostatin Analogs ◽  
Normal Serum ◽  
Gh Receptor ◽  
Level Increase ◽  
Gh Receptor Antagonist ◽  
Extrahepatic Tissues ◽  
High Doses ◽  
The Impact

After the introduction of somatostatin analogs (LA-SMSA) and the growth hormone (GH) receptor antagonist, pegvisomant (Peg-v) normal serum insulin-like growth factor-1 (IGF-1) concentrations in virtually every patients with acromegaly is possible. The impact of these products on the GH–IGF1 axis is completely different. We advocate that LA-SMSA may normalize serum IGF1 levels in the presence of elevated GH actions in extrahepatic tissues. This results in persistent peripheral disease activity that we call ‘extra-hepatic acromegaly’. Peg-v competitively blocks systemic GH action and results in a GH serum level increase. Therefore high doses of Peg-v are necessary to control IGF-1. Since the mode of action differs between these products, it is questionable if identical IGF-1 levels, during Peg-v or LA-SMSA are really identical representations of the biochemical situation. With the traditional biomarkers medical treatment is therefore difficult to monitor with the traditional biomarkers. Additionally, Peg-v and LA-SMSA could be ideal combination since they have different mode of actions. We believe that the time has come to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

scholarly journals Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

2009 ◽  
Vol 161 (4) ◽  
pp. 639-645 ◽  
Author(s):  
Thomas Walter ◽  
Laurence Chardon ◽  
Valérie Hervieu ◽  
Richard Cohen ◽  
Jean-Alain Chayvialle ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Tissue Expression ◽  
Primary Tumors ◽  
Disease Characteristics ◽  
Total Ghrelin ◽  
Functional Consequences ◽  
Acyl Ghrelin ◽  
Well Differentiated ◽  
Serum Ghrelin ◽  
Neuroendocrine Carcinomas

ObjectiveWe aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution.DesignWe retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin.MethodsBetween February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (n=72). Three patients were found to have circulating ghrelin levels >10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry.ResultsThe three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with <10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia.ConclusionWell-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.

Diagnosis and Management of Acromegaly in 2014 (Update from 2012)

2014 ◽  
Vol 10 (02) ◽  
pp. 120
Author(s):  
Laurence Katznelson ◽  
Keyword(s):  
Tumor Growth ◽  
Medical Therapy ◽  
De Novo ◽  
Therapeutic Option ◽  
Somatostatin Receptor ◽  
Premature Mortality ◽  
Gh Secretion ◽  
Gh Receptor Antagonist ◽  
Multimodality Approach ◽  
Somatostatin Receptor Ligand

In this update to the 2012 summary, the current diagnostic and therapeutic approaches to acromegaly are reviewed. The goals of therapy are to control excess growth hormone (GH) secretion and tumor growth, and to limit, if not reverse, the long-term medical consequences and risk for premature mortality associated with acromegaly. Surgery is the preferred primary therapeutic option because it can lead to rapid reductions in GH levels and prevent mass effects from local tumor growth. Use of a somatostatin receptor ligand (SRL) preoperatively to improve surgical outcomes has not been substantiated. Medical therapy, including SRLs, dopamine agonists, and the GH receptor antagonist pegvisomant, is used most often in an adjuvant, secondary role for patients in whom surgery has been unsuccessful. Radiation therapy is most commonly recommended in the setting of failed surgery and lack of adequate control with medical therapy. A role of primary medical therapy for de novo patients has been proposed, particularly with SRLs. Using a multimodality approach, successful management of the disease and associated consequences should be achieved in the majority of subjects.

scholarly journals Inactivation of thyA in Staphylococcus aureus Attenuates Virulence and Has a Strong Impact on Metabolism and Virulence Gene Expression

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Andre Kriegeskorte ◽  
Desiree Block ◽  
Mike Drescher ◽  
Nadine Windmüller ◽  
Alexander Mellmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Thymidylate Synthase ◽  
Molecular Basis ◽  
De Novo ◽  
Strong Impact ◽  
Small Colony Variants ◽  
Content Type ◽  
Long Term Treatment ◽  
Small Colony ◽  
The Impact

ABSTRACTStaphylococcus aureusthymidine-dependent small-colony variants (TD-SCVs) are frequently isolated from patients with chronicS. aureusinfections after long-term treatment with trimethoprim-sulfamethoxazole (TMP-SMX). While it has been shown that TD-SCVs were associated with mutations in thymidylate synthase (TS;thyA), the impact of such mutations on protein function is lacking. In this study, we showed that mutations inthyAwere leading to inactivity of TS proteins, and TS inactivity led to tremendous impact onS. aureusphysiology and virulence. Whole DNA microarray analysis of the constructed ΔthyAmutant identified severe alterations compared to the wild type. Important virulence regulators (agr,arlRS,sarA) and major virulence determinants (hla,hlb,sspAB, andgeh) were downregulated, while genes important for colonization (fnbA,fnbB,spa,clfB,sdrC, andsdrD) were upregulated. The expression of genes involved in pyrimidine and purine metabolism and nucleotide interconversion changed significantly. NupC was identified as a major nucleoside transporter, which supported growth of the mutant during TMP-SMX exposure by uptake of extracellular thymidine. The ΔthyAmutant was strongly attenuated in virulence models, including aCaenorhabditis eleganskilling model and an acute pneumonia mouse model. This study identified inactivation of TS as the molecular basis of clinical TD-SCV and showed thatthyAactivity has a major role forS. aureusvirulence and physiology.IMPORTANCEThymidine-dependent small-colony variants (TD-SCVs) ofStaphylococcus aureuscarry mutations in the thymidylate synthase (TS) gene (thyA) responsible forde novosynthesis of thymidylate, which is essential for DNA synthesis. TD-SCVs have been isolated from patients treated for long periods with trimethoprim-sulfamethoxazole (TMP-SMX) and are associated with chronic and recurrent infections. In the era of community-associated methicillin-resistantS. aureus, the therapeutic use of TMP-SMX is increasing. Today, the emergence of TD-SCVs is still underestimated due to misidentification in the diagnostic laboratory. This study showed for the first time that mutational inactivation of TS is the molecular basis for the TD-SCV phenotype and that TS inactivation has a strong impact onS. aureusvirulence and physiology. Our study helps to understand the clinical nature of TD-SCVs, which emerge frequently once patients are treated with TMP-SMX.

Receptor-Based Models with Diffusion-Driven Instability for Pattern Formation in Hydra

2003 ◽  
Vol 11 (03) ◽  
pp. 293-324 ◽  
Author(s):  
Anna Marciniak-Czochra
Keyword(s):  
Pattern Formation ◽  
Feedback Loop ◽  
De Novo ◽  
Initial Conditions ◽  
Reaction Diffusion ◽  
Reaction Diffusion Equations ◽  
Variable Model ◽  
Dissociated Cells ◽  
Cutting Experiments ◽  
Positional Value

The aim of this paper is to show under which conditions a receptor-based model can produce and regulate patterns. Such model is applied to the pattern formation and regulation in a fresh water polyp, hydra. The model is based on the idea that both head and foot formation could be controlled by receptor-ligand binding. Positional value is determined by the density of bound receptors. The model is defined in the form of reaction-diffusion equations coupled with ordinary differential equations. The objective is to check what minimal processes are sufficient to produce patterns in the framework of a diffusion-driven (Turing-type) instability. Three-variable (describing the dynamics of ligands, free and bound receptors) and four-variable models (including also an enzyme cleaving the ligand) are analyzed and compared. The minimal three-variable model takes into consideration the density of free receptors, bound receptors and ligands. In such model patterns can evolve only if self-enhancement of free receptors, i.e., a positive feedback loop between the production of new free receptors and their present density, is assumed. The final pattern strongly depends on initial conditions. In the four-variable model a diffusion-driven instability occurs without the assumption that free receptors stimulate their own synthesis. It is shown that gradient in the density of bound receptors occurs if there is also a second diffusible substance, an enzyme, which degrades ligands. Numerical simulations are done to illustrate the analysis. The four-variable model is able to capture some results from cutting experiments and reflects de novo pattern formation from dissociated cells.

scholarly journals Excavation and aggregation as organizing factors in de novo construction by mound-building termites

2017 ◽  
Vol 284 (1856) ◽  
pp. 20162730 ◽  
Author(s):  
Ben Green ◽  
Paul Bardunias ◽  
J. Scott Turner ◽  
Radhika Nagpal ◽  
Justin Werfel
Keyword(s):  
Feedback Loop ◽  
De Novo ◽  
Early Stage ◽  
Agent Based ◽  
Functional Roles ◽  
Mound Construction ◽  
Aggregation Activity ◽  
Future Work ◽  
Excavation Site ◽  
Traditional Understanding

Termites construct complex mounds that are orders of magnitude larger than any individual and fulfil a variety of functional roles. Yet the processes through which these mounds are built, and by which the insects organize their efforts, remain poorly understood. The traditional understanding focuses on stigmergy, a form of indirect communication in which actions that change the environment provide cues that influence future work. Termite construction has long been thought to be organized via a putative ‘cement pheromone’: a chemical added to deposited soil that stimulates further deposition in the same area, thus creating a positive feedback loop whereby coherent structures are built up. To investigate the detailed mechanisms and behaviours through which termites self-organize the early stages of mound construction, we tracked the motion and behaviour of major workers from two Macrotermes species in experimental arenas. Rather than a construction process focused on accumulation of depositions, as models based on cement pheromone would suggest, our results indicated that the primary organizing mechanisms were based on excavation. Digging activity was focused on a small number of excavation sites, which in turn provided templates for soil deposition. This behaviour was mediated by a mechanism of aggregation, with termites being more likely to join in the work at an excavation site as the number of termites presently working at that site increased. Statistical analyses showed that this aggregation mechanism was a response to active digging, distinct from and unrelated to putative chemical cues that stimulate deposition. Agent-based simulations quantitatively supported the interpretation that the early stage of de novo construction is primarily organized by excavation and aggregation activity rather than by stigmergic deposition.

Growth Hormone Receptor Antagonist Therapy in Acromegalic Patients Resistant to Somatostatin Analogs*

2000 ◽  
Vol 85 (8) ◽  
pp. 2958-2961 ◽  
Author(s):  
Vivien S. Herman-Bonert ◽  
Kenneth Zib ◽  
John A. Scarlett ◽  
Shlomo Melmed
Keyword(s):  
Growth Hormone ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Growth Hormone Secretion ◽  
Primary Therapy ◽  
Gh Receptor ◽  
Gh Receptor Antagonist ◽  
Octreotide Therapy

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant—three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10–20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.

scholarly journals Pituitary hormones are specifically expressed in trigeminal sensory neurons and contribute to pain responses in the trigeminal system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anahit H. Hovhannisyan ◽  
Hyeonwi Son ◽  
Jennifer Mecklenburg ◽  
Priscilla Ann Barba-Escobedo ◽  
Meilinn Tram ◽  
...  
Keyword(s):  
Pituitary Hormones ◽  
Trigeminal System ◽  
Pituitary Hormone ◽  
Drg Neurons ◽  
Mechanical Hypersensitivity ◽  
Gh Receptor ◽  
Gh Receptor Antagonist ◽  
Ganglion Neurons ◽  
Thermal Hypersensitivity ◽  
Encoding Genes

AbstractTrigeminal (TG), dorsal root (DRG), and nodose/jugular (NG/JG) ganglia each possess specialized and distinct functions. We used RNA sequencing of two-cycle sorted Pirt-positive neurons to identify genes exclusively expressing in L3–L5 DRG, T10-L1 DRG, NG/JG, and TG mouse ganglion neurons. Transcription factor Phox2b and Efcab6 are specifically expressed in NG/JG while Hoxa7 is exclusively present in both T10-L1 and L3–L5 DRG neurons. Cyp2f2, Krt18, and Ptgds, along with pituitary hormone prolactin (Prl), growth hormone (Gh), and proopiomelanocortin (Pomc) encoding genes are almost exclusively in TG neurons. Immunohistochemistry confirmed selective expression of these hormones in TG neurons and dural nerves; and showed GH expression in subsets of TRPV1+ and CGRP+ TG neurons. We next examined GH roles in hypersensitivity in the spinal versus trigeminal systems. Exogenous GH produced mechanical hypersensitivity when injected intrathecally, but not intraplantarly. GH-induced thermal hypersensitivity was not detected in the spinal system. GH dose-dependently generated orofacial and headache-like periorbital mechanical hypersensitivity after administration into masseter muscle and dura, respectively. Periorbital mechanical hypersensitivity was reversed by a GH receptor antagonist, pegvisomant. Overall, pituitary hormone genes are selective for TG versus other ganglia somatotypes; and GH has distinctive functional significance in the trigeminal versus spinal systems.

Impact of the GH-receptor antagonist pegvisomant on mammographic breast density in postmenopausal acromegalic women

2016 ◽  
Author(s):  
Ammar Muhammad ◽  
Gianluca Ficarra ◽  
Sanne Franck ◽  
Elena Nazarri ◽  
Alberto Tagliafico ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Breast Density ◽  
Mammographic Breast Density ◽  
Gh Receptor ◽  
Gh Receptor Antagonist
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