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Henning Dralle - One of the best experts on this subject based on the ideXlab platform.

  • HyperCalcitoninemia in thyroid conditions other than medullary thyroid carcinoma: a comparative analysis of calcium and pentagastrin stimulation of serum Calcitonin
    Langenbeck's Archives of Surgery, 2013
    Co-Authors: Kerstin Lorenz, Andreas Machens, Malik Elwerr, Mohammed Abuazab, Hans-jürgen Holzhausen, Henning Dralle
    Abstract:

    Purpose Calcitonin screening aims at uncovering occult medullary thyroid cancer (MTC) in patients with nodular thyroid disease. Elevated basal Calcitonin serum levels call for Calcitonin stimulation, the level of which may direct the extent of surgery. Because pentagastrin has become restricted, calcium has increasingly been used instead for stimulation. This study identified a new spectrum of patients demonstrating a false-positive hyperCalcitoninemia in the absence of C-cell disease, carrying multinodular goiter (MNG), thyroiditis, and non-MTC thyroid malignancy, and endeavored to explore the feasibility of extrapolating pentagastrin-stimulated to calcium-stimulated Calcitonin thresholds. Methods Altogether, 43 (9.5 %) of 455 patients with nodular thyroid disease revealed increased basal Calcitonin serum levels between 2005 and 2012, for which they underwent intravenous stimulation with pentagastrin (31 patients) or calcium gluconate (12 patients) before and after primary thyroidectomy. Results Stimulation with calcium gluconate resulted in significantly higher and more variable preoperative Calcitonin serum levels after 2 (241.2 vs. 104.9 pg/mL; P  = 0.018) and 5 min (240.6 vs. 87.4 pg/mL; P  = 0.007) than stimulation with pentagastrin. Stimulation with calcium gluconate produced 10-fold (nodular goiter), 15-fold (thyroiditis), and 21-fold (thyroid neoplasia other than MTC) Calcitonin increases over baseline, as opposed to 5-fold, 10-fold, and 8-fold increases after stimulation with pentagastrin. None of the 43 patients, all of whom reverted to undetectable Calcitonin serum levels after thyroidectomy, had immunohistochemical evidence of C-cell disease. Subgroup analyses according to gender and thyroid disease, being limited by the low number of patients in each subgroup, did not yield significant differences. Conclusions Calcium stimulation yields significantly greater Calcitonin levels than pentagastrin stimulation, precluding generalization of pentagastrin-stimulated to calcium-stimulated Calcitonin thresholds. After calcium stimulation, false-positive findings appear to be more common in patients of female gender and patients with thyroiditis and thyroid neoplasia other than MTC, potentially effecting surgical overtreatment.

  • importance of gender specific Calcitonin thresholds in screening for occult sporadic medullary thyroid cancer
    Endocrine-related Cancer, 2009
    Co-Authors: Andreas Machens, Florian Hoffmann, C Sekulla, Henning Dralle
    Abstract:

    Men and women differ in thyroidal C-cell mass and Calcitonin secretion. This difference may have implications for the definition of Calcitonin thresholds to distinguish sporadic C-cell hyperplasia from occult medullary thyroid cancer. This retrospective study examined the hypothesis that gender-specific Calcitonin thresholds predict occult medullary thyroid cancer more accurately among patients with increased basal Calcitonin levels than unisex thresholds. A total of 100 consecutive patients were evaluated with occult sporadic C-cell disease no larger than 10 mm who were referred for increased basal Calcitonin levels and underwent pentagastrin stimulation preoperatively at this institution. Altogether, gender-specific Calcitonin thresholds predicted medullary thyroid cancer better than unisex thresholds. At lower (Calcitonin serum levels, women revealed medullary thyroid cancer four to eight times more often than men. Most discriminatory between C-cell hyperplasia and medullary thyroid cancer was a basal Calcitonin threshold of 15 pg/ml (corrected 20 pg/ml) for women and 80 pg/ml (corrected 100 pg/ml) for men, based on the greatest accuracy at the lowest possible Calcitonin level. The respective gender-specific stimulated peak Calcitonin thresholds were 80 pg/ml (corrected 100 pg/ml) and 500 pg/ml. Corresponding positive predictive values for medullary thyroid cancer at these Calcitonin thresholds were 89 and 90% for women, as opposed to 100% for men. To increase the positive predictive value for women to 100%, the respective Calcitonin thresholds would have to be raised to 40 pg/ml (corrected 50 pg/ml) and 250 pg/ml. These findings indicate that gender-specific Calcitonin thresholds predict sporadic occult medullary thyroid cancer better than unisex thresholds.

  • prospects of remission in medullary thyroid carcinoma according to basal Calcitonin level
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Andreas Machens, Ulrich Schneyer, H J Holzhausen, Henning Dralle
    Abstract:

    Prediction of remission in medullary thyroid carcinoma (MTC) depends on histopathological information often unavailable before surgery. Simply requiring a venous blood sample, preoperative basal Calcitonin levels may be a better indicator of remission. In this institutional series of 224 consecutive patients with MTC and elevated preoperative basal Calcitonin levels, postoperative Calcitonin levels normalized in 28 (62%) of 45 patients with node-negative MTC and in 18 (10%) of 177 patients with node-positive MTC. On multivariate analysis, preoperative basal Calcitonin levels greater than 500 pg/ml best predicted the failure to achieve biochemical remission, followed by nodal metastasis and reoperative status. Cumulative rates of biochemical remission fell continuously with rising serum basal Calcitonin in node-negative patients. Node-positive patients did not achieve biochemical remission when their preoperative basal Calcitonin levels exceeded 3000 pg/ml. Nodal metastasis started emerging at basal Calcitonin levels of 10-40 pg/ml (normal range, <10 pg/ml). Distant metastasis and extrathyroidal growth began appearing in patients with node-positive MTC at basal Calcitonin levels of 150-400 pg/ml. There were no differences between patients with sporadic and hereditary MTC after adjusting for multiple testing. Preoperative basal Calcitonin levels may thus help individualize the extent of surgery and postoperative follow-up intervals for MTC.

Patrick M. Sexton - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Pharmacology of the Calcitonin Receptor
    Receptors & Channels, 2011
    Co-Authors: Brooke W Purdue, Nandasena Tilakaratne, Patrick M. Sexton
    Abstract:

    The peptide hormone Calcitonin is widely used therapeutically in the treatment of bone disorders such as Paget's disease, osteoporosis, and the hypercalcemia of some malignancies. However, emerging evidence suggests the actions of Calcitonin via its G protein-coupled receptor, the Calcitonin receptor, may not be limited to bone. Calcitonin receptors have also been identified in the central nervous system, testes, skeletal muscle, lymphocytes, and the placenta. We are now becoming aware that the complexity of the Calcitonin response mediated by the Calcitonin receptor can be influenced by accessory proteins, receptor isoforms, genetic polymorphisms, developmental and/or transcriptional regulation, feedback inhibition, and the specific cellular or tissue background. This article discusses what is known about the molecular and pharmacological actions of the Calcitonin receptor and highlights areas of current research.

  • pharmacological discrimination of Calcitonin receptor receptor activity modifying protein complexes
    Molecular Pharmacology, 2005
    Co-Authors: Debbie L Hay, George Christopoulos, Arthur Christopoulos, David R Poyner, Patrick M. Sexton
    Abstract:

    Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT (a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of αCGRP, being a weak agonist at CT(a), AMY 2(a), and AMY3(a) receptors but considerably more potent at AMY1(a) receptors. Likewise, the linear Calcitonin gene-related peptide (CGRP) analogs (Cys(ACM)2,7)hαCGRP and (Cys(Et) 2,7)haCGRP were only effective at AMY1(a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY2(a) receptor phenotype; thus, AMY 2(a) was not examined further in this study. The antagonist peptide salmon Calcitonin8-32 (sCT8-32) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY1(a) over AMY3(a) receptors. CGRP8-37 also demonstrated receptor-dependent effects. CGRP 8-37 more effectively antagonized AMY at AMY1(a) than AMY3(a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT(a) receptor. Low CGRP 8-37 affinity and agonism by linear CGRP analogs at AMY 1(a) are the classic signature of a CGRP2 receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT(a), AMY1(a), and AMY3(a) receptors, providing a means to delineate the physiological significance of these receptors. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.

  • Evidence for a new subclass of Calcitonin/ Calcitonin gene-related peptide binding site in rat brain.
    Neurochemistry International, 2003
    Co-Authors: Patrick M. Sexton, J.s. Mckenzie, Frederick A.o. Mendelsohn
    Abstract:

    Abstract Binding sites for Calcitonin and Calcitonin gene-related peptide are widely distributed in the central nervous system. In this study, binding of [ 125 I]-alpha-rat Calcitonin gene-related peptide and [ 125 I]-salmon Calcitonin in adjacent sections of rat brain revealed clearly distinct patterns of binding in most regions although in some restricted areas such as parts of the ventral striatum, including the nucleus accumbens, there was some overlap in the patterns of binding. In the primary olfactory cortex, which bound only Calcitonin gene-related peptide, salmon Calcitonin was very weak in inhibiting the binding of Calcitonin gene-related peptide. In the nucleus accumbens, high affinity binding of Calcitonin and Calcitonin gene-related peptide at their homologous receptors was observed, with affinity constants for Calcitonin and Calcitonin gene-related peptide of 1.4 × 10 9 M −1 and 1.2 × 10 9 M −1 respectively. Cross competition studies in this nucleus demonstrated that salmon Calcitonin was able to compete for [ 125 I]-rat Calcitonin gene-related peptide labelled sites with high affinity, with an affinity constant of 0.8 × 10 9 M −1 . However, rat Calcitonin gene-related peptide was less potent in inhibiting the binding of [ 125 I]-salmon Calcitonin labelled sites with only 28% inhibition at 10 −6 M. Further characterization of the Calcitonin sensitive Calcitonin gene-related peptide labelled sites demonstrated that a range of Calcitonin analogs inhibited the binding of [ 125 I]-rat Calcitonin gene-related peptide with the same order of potency as the analogs competed for [ 125 I]-salmon Calcitonin labelled sites. Digital substraction mapping revealed Calcitonin-sensitive Calcitonin gene-related peptide binding sites over parts of the ventral striatum, including mid-caudal nucleus accumbens and fundus striati; over the lateral border of the lateral bed nucleus of the stria terminalis; part of the central amygdaloid nucleus; the organum vasculosum of the lamina terminalis and area postrema and over the wings of the dorsal raphe. These results demonstrate the existence of a new subtype of Calcitonin/Calcitonin gene-related peptide binding site, which has high affinity for the two otherwise biochemically distinct peptides.

  • international union of pharmacology xxxii the mammalian Calcitonin gene related peptides adrenomedullin amylin and Calcitonin receptors
    Pharmacological Reviews, 2002
    Co-Authors: David R Poyner, Jan A. Fischer, Patrick M. Sexton, Walter Born, Ian W Marshall, David M Smith, Remi Quirion, Roman Muff, Steven M Foord
    Abstract:

    The Calcitonin family of peptides comprises Calcitonin, amylin two Calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first Calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The Calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the Calcitonin receptor does not require RAMP to bind and respond to Calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.

Andreas Machens - One of the best experts on this subject based on the ideXlab platform.

  • HyperCalcitoninemia in thyroid conditions other than medullary thyroid carcinoma: a comparative analysis of calcium and pentagastrin stimulation of serum Calcitonin
    Langenbeck's Archives of Surgery, 2013
    Co-Authors: Kerstin Lorenz, Andreas Machens, Malik Elwerr, Mohammed Abuazab, Hans-jürgen Holzhausen, Henning Dralle
    Abstract:

    Purpose Calcitonin screening aims at uncovering occult medullary thyroid cancer (MTC) in patients with nodular thyroid disease. Elevated basal Calcitonin serum levels call for Calcitonin stimulation, the level of which may direct the extent of surgery. Because pentagastrin has become restricted, calcium has increasingly been used instead for stimulation. This study identified a new spectrum of patients demonstrating a false-positive hyperCalcitoninemia in the absence of C-cell disease, carrying multinodular goiter (MNG), thyroiditis, and non-MTC thyroid malignancy, and endeavored to explore the feasibility of extrapolating pentagastrin-stimulated to calcium-stimulated Calcitonin thresholds. Methods Altogether, 43 (9.5 %) of 455 patients with nodular thyroid disease revealed increased basal Calcitonin serum levels between 2005 and 2012, for which they underwent intravenous stimulation with pentagastrin (31 patients) or calcium gluconate (12 patients) before and after primary thyroidectomy. Results Stimulation with calcium gluconate resulted in significantly higher and more variable preoperative Calcitonin serum levels after 2 (241.2 vs. 104.9 pg/mL; P  = 0.018) and 5 min (240.6 vs. 87.4 pg/mL; P  = 0.007) than stimulation with pentagastrin. Stimulation with calcium gluconate produced 10-fold (nodular goiter), 15-fold (thyroiditis), and 21-fold (thyroid neoplasia other than MTC) Calcitonin increases over baseline, as opposed to 5-fold, 10-fold, and 8-fold increases after stimulation with pentagastrin. None of the 43 patients, all of whom reverted to undetectable Calcitonin serum levels after thyroidectomy, had immunohistochemical evidence of C-cell disease. Subgroup analyses according to gender and thyroid disease, being limited by the low number of patients in each subgroup, did not yield significant differences. Conclusions Calcium stimulation yields significantly greater Calcitonin levels than pentagastrin stimulation, precluding generalization of pentagastrin-stimulated to calcium-stimulated Calcitonin thresholds. After calcium stimulation, false-positive findings appear to be more common in patients of female gender and patients with thyroiditis and thyroid neoplasia other than MTC, potentially effecting surgical overtreatment.

  • importance of gender specific Calcitonin thresholds in screening for occult sporadic medullary thyroid cancer
    Endocrine-related Cancer, 2009
    Co-Authors: Andreas Machens, Florian Hoffmann, C Sekulla, Henning Dralle
    Abstract:

    Men and women differ in thyroidal C-cell mass and Calcitonin secretion. This difference may have implications for the definition of Calcitonin thresholds to distinguish sporadic C-cell hyperplasia from occult medullary thyroid cancer. This retrospective study examined the hypothesis that gender-specific Calcitonin thresholds predict occult medullary thyroid cancer more accurately among patients with increased basal Calcitonin levels than unisex thresholds. A total of 100 consecutive patients were evaluated with occult sporadic C-cell disease no larger than 10 mm who were referred for increased basal Calcitonin levels and underwent pentagastrin stimulation preoperatively at this institution. Altogether, gender-specific Calcitonin thresholds predicted medullary thyroid cancer better than unisex thresholds. At lower (Calcitonin serum levels, women revealed medullary thyroid cancer four to eight times more often than men. Most discriminatory between C-cell hyperplasia and medullary thyroid cancer was a basal Calcitonin threshold of 15 pg/ml (corrected 20 pg/ml) for women and 80 pg/ml (corrected 100 pg/ml) for men, based on the greatest accuracy at the lowest possible Calcitonin level. The respective gender-specific stimulated peak Calcitonin thresholds were 80 pg/ml (corrected 100 pg/ml) and 500 pg/ml. Corresponding positive predictive values for medullary thyroid cancer at these Calcitonin thresholds were 89 and 90% for women, as opposed to 100% for men. To increase the positive predictive value for women to 100%, the respective Calcitonin thresholds would have to be raised to 40 pg/ml (corrected 50 pg/ml) and 250 pg/ml. These findings indicate that gender-specific Calcitonin thresholds predict sporadic occult medullary thyroid cancer better than unisex thresholds.

  • prospects of remission in medullary thyroid carcinoma according to basal Calcitonin level
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Andreas Machens, Ulrich Schneyer, H J Holzhausen, Henning Dralle
    Abstract:

    Prediction of remission in medullary thyroid carcinoma (MTC) depends on histopathological information often unavailable before surgery. Simply requiring a venous blood sample, preoperative basal Calcitonin levels may be a better indicator of remission. In this institutional series of 224 consecutive patients with MTC and elevated preoperative basal Calcitonin levels, postoperative Calcitonin levels normalized in 28 (62%) of 45 patients with node-negative MTC and in 18 (10%) of 177 patients with node-positive MTC. On multivariate analysis, preoperative basal Calcitonin levels greater than 500 pg/ml best predicted the failure to achieve biochemical remission, followed by nodal metastasis and reoperative status. Cumulative rates of biochemical remission fell continuously with rising serum basal Calcitonin in node-negative patients. Node-positive patients did not achieve biochemical remission when their preoperative basal Calcitonin levels exceeded 3000 pg/ml. Nodal metastasis started emerging at basal Calcitonin levels of 10-40 pg/ml (normal range, <10 pg/ml). Distant metastasis and extrathyroidal growth began appearing in patients with node-positive MTC at basal Calcitonin levels of 150-400 pg/ml. There were no differences between patients with sporadic and hereditary MTC after adjusting for multiple testing. Preoperative basal Calcitonin levels may thus help individualize the extent of surgery and postoperative follow-up intervals for MTC.

David R Poyner - One of the best experts on this subject based on the ideXlab platform.

  • pharmacological discrimination of Calcitonin receptor receptor activity modifying protein complexes
    Molecular Pharmacology, 2005
    Co-Authors: Debbie L Hay, George Christopoulos, Arthur Christopoulos, David R Poyner, Patrick M. Sexton
    Abstract:

    Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT (a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of αCGRP, being a weak agonist at CT(a), AMY 2(a), and AMY3(a) receptors but considerably more potent at AMY1(a) receptors. Likewise, the linear Calcitonin gene-related peptide (CGRP) analogs (Cys(ACM)2,7)hαCGRP and (Cys(Et) 2,7)haCGRP were only effective at AMY1(a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY2(a) receptor phenotype; thus, AMY 2(a) was not examined further in this study. The antagonist peptide salmon Calcitonin8-32 (sCT8-32) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY1(a) over AMY3(a) receptors. CGRP8-37 also demonstrated receptor-dependent effects. CGRP 8-37 more effectively antagonized AMY at AMY1(a) than AMY3(a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT(a) receptor. Low CGRP 8-37 affinity and agonism by linear CGRP analogs at AMY 1(a) are the classic signature of a CGRP2 receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT(a), AMY1(a), and AMY3(a) receptors, providing a means to delineate the physiological significance of these receptors. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.

  • international union of pharmacology xxxii the mammalian Calcitonin gene related peptides adrenomedullin amylin and Calcitonin receptors
    Pharmacological Reviews, 2002
    Co-Authors: David R Poyner, Jan A. Fischer, Patrick M. Sexton, Walter Born, Ian W Marshall, David M Smith, Remi Quirion, Roman Muff, Steven M Foord
    Abstract:

    The Calcitonin family of peptides comprises Calcitonin, amylin two Calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first Calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The Calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the Calcitonin receptor does not require RAMP to bind and respond to Calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.

Steven M Foord - One of the best experts on this subject based on the ideXlab platform.

  • international union of pharmacology xxxii the mammalian Calcitonin gene related peptides adrenomedullin amylin and Calcitonin receptors
    Pharmacological Reviews, 2002
    Co-Authors: David R Poyner, Jan A. Fischer, Patrick M. Sexton, Walter Born, Ian W Marshall, David M Smith, Remi Quirion, Roman Muff, Steven M Foord
    Abstract:

    The Calcitonin family of peptides comprises Calcitonin, amylin two Calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first Calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The Calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the Calcitonin receptor does not require RAMP to bind and respond to Calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.