Calcitonin
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Location (UCSC) | Chr 11: 14.97 – 14.97 Mb | n/a | |||||||
PubMed search | [2] | n/a |
View/Edit Human |
Calcitonin is a 32
Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal
Historically calcitonin has also been called thyrocalcitonin.[7]
Biosynthesis and regulation
Calcitonin is formed by the
Secretion of calcitonin is stimulated by:
- an increase in serum Calcium [Ca2+][8]
- gastrin and pentagastrin.[9]
Function
The hormone participates in calcium (Ca2+) metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH) and vitamin D.
More specifically, calcitonin lowers blood Ca2+ levels in two ways:
- Major effect: Inhibits osteoclast activity in bones, which break down the bone[10]
- Minor effect: Inhibits renal tubular cell reabsorption of Ca2+ and phosphate, allowing them to be excreted in the urine[11][12]
High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate via the renal tubules.[13] leading to marked hypocalcemia. However, this is a minor effect with no physiological significance in humans. It is also a short-lived effect because the kidneys become resistant to calcitonin, as demonstrated by the kidney's unaffected excretion of calcium in patients with thyroid tumors that secrete excessive calcitonin.[14]
In its skeleton-preserving actions, calcitonin protects against calcium loss from the skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. The protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of the release of prolactin from the pituitary gland. The reason provided is that prolactin induces the release of PTH related peptide which enhances bone resorption, but is still under investigation.[15][16][17]
Other effects are in preventing postprandial
Calcitonin lowers blood calcium and phosphorus mainly through its inhibition of osteoclasts.
Receptor
The
Discovery
Calcitonin was first purified in 1962 by
Clinical significance
Calcitonin assay is used in identifying patients with nodular
Calcitonin also has significantly impacted
Pharmacology
Calcitonin has clinically been used for metabolic bone disorders for more than 50 years.[23] Salmon calcitonin is used for the treatment of:
- Postmenopausal osteoporosis[24]
- Hypercalcaemia[25]
- Bone metastases[26]
- Paget's disease[27]
- Phantom limb pain[28]
It has been investigated as a possible non-operative treatment for spinal stenosis.[29]
The following information is from the UK Electronic Medicines Compendium[30]
General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage kidney failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.
Preclinical safety data
Conventional long-term toxicity, reproduction,
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance.[31] Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
Pharmaceutical manufacture
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon.
Uses of calcitonin
Treatments
Calcitonin can be used therapeutically for the treatment of
Subcutaneous injections of calcitonin in patients with mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.[34] However no further work on this potential application of calcitonin has been reported.
Diagnostics
It may be used diagnostically as a
- females: 5 ng/L or pg/mL
- males: 12 ng/L or pg/mL
- children under 6 months of age: 40 ng/L or pg/mL
- children between 6 months and 3 years of age: 15 ng/L or pg/mL
When over 3 years of age, adult cutoffs may be used
A Cochrane systematic review assessed the diagnostic accuracy of basal and stimulated calcitonin for Medullary Thyroid cancer.[36] Although both basal and combined basal and stimulated calcitonin testing presented high accuracy (sensitivity: between 82% and 100%; specificity: between 97.2% and 100%), these results had a high risk of bias due to design flaws of included studies.[36] Overall, the value of routine testing of calcitonin for diagnosis and prognosis of Medullary Thyroid Cancer remains uncertain and questionable.[36]
Increased levels of calcitonin have also been reported for various other conditions. They include:
Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.[38] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.[39]
The following are the amino acid sequences of salmon and human calcitonin:[citation needed][40]
- salmon:
Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro
- human:
Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro
Compared to salmon calcitonin, human calcitonin differs at 16 residues.
Research
In addition to the injectable and nasal spray dosage forms of the salmon calcitonin, noninvasive oral formulations of the peptide are currently under clinical development. The short-half-life of this peptide in serum triggered several attempts to enhance plasma concentrations. The peptide is complexed with a macromolecule that acts as an absorption enhancer through the transcellular pathway and, additionally, protects the peptide from the harsh pH and enzymatic conditions of the GI tract. This complexation is weak, noncovalent and reversible and the drug remains chemically unmodified. After passage through the intestine, the delivery agent dissociates from the peptide. One of the extensively studied oral formulations is the disodium salts of 5-CNAC oral calcitonin. This novel oral platform in a number of clinical trials at different phases has demonstrated promising enhanced pharmacokinetic profile, high bioavailability, well-established safety and comparable efficacy to that of nasal calcitonin especially for treatment of postmenopausal bone loss.[23]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000110680 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 26644465.
- ^ Costoff A. "Sect. 5, Ch. 6: Anatomy, Structure, and Synthesis of Calcitonin (CT)". Endocrinology: hormonal control of calcium and phosphate. Medical College of Georgia. Archived from the original on September 5, 2008. Retrieved 2008-08-07.
- ISBN 1416023283.
- ^ Costoff A. "Sect. 5, Ch. 6: Biological Actions of CT". Medical College of Georgia. Archived from the original on July 5, 2008. Retrieved 2008-08-07.
- PMID 25815174.
- ISBN 978-0-7817-7311-9.
- S2CID 41798141.
- ^ Costoff A. "Sect. 5, Ch. 6: Effects of CT on Bone". Medical College of Georgia. Archived from the original on June 22, 2008. Retrieved 2008-08-07.
- ^ Potts J, Jüppner H (2008). "Chapter 353. Disorders of the Parathyroid Gland and Calcium Homeostasis". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. Archived from the original on 2017-05-08. Retrieved 2017-05-29.
- ISBN 978-0781768528.[page needed]
- PMID 9058369.
- ^ ISBN 978-0123739759.[page needed]
- S2CID 25594820.
- PMID 18627265.
- PMID 16675524.
- PMID 3016026.
- ^ S2CID 4292938.
- S2CID 2443410.
- S2CID 4318349.
- PMID 6952224.
- ^ ISBN 978-1461495246.
- NIAMS. August 2014. Archivedfrom the original on 18 May 2015. Retrieved 16 May 2015.
- ^ "Hypercalcemia". The Lecturio Medical Concept Library. Retrieved 1 October 2021.
- ^ MedlinePlus Overview bonecancer
- ^ "Paget's Disease of Bone". The Lecturio Medical Concept Library. Retrieved 1 October 2021.
- S2CID 30651328.
- PMID 20428988.
- ^ a b "Electronic Medicines Compendium". Archived from the original on 2005-11-08. Retrieved 2008-08-07.
- ^ "Injectable Salmon Calcitonin" (PDF). Archived from the original (PDF) on 2018-06-18. Retrieved 2017-02-07.
- S2CID 23551343.
- PMID 25410076.
- PMID 9549251.
- PMID 15388660.
- ^ PMID 32176812.
- ISBN 978-1-4160-6164-9.
- PMID 16766525.
- ^ "calcitonin domain annotation". SMART (a Simple Modular Architecture Research Tool). embl-heidelberg.de. Retrieved 2009-02-22.
- ^ "Salmon calicitonin". prospecbio.
Further reading
- MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M (April 1987). "Calcitonin and the peptides from the calcitonin gene". Clinical Orthopaedics and Related Research. 217 (217): 45–55. PMID 3549095.
- Di Angelantonio S, Giniatullin R, Costa V, Sokolova E, Nistri A (July 2003). "Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells". British Journal of Pharmacology. 139 (6): 1061–1073. PMID 12871824.
- Findlay DM, Sexton PM (December 2004). "Calcitonin". Growth Factors. 22 (4): 217–224. S2CID 218910711.
- Sponholz C, Sakr Y, Reinhart K, Brunkhorst F (2007). "Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature". Critical Care. 10 (5): R145. PMID 17038199.
- Schneider HG, Lam QT (August 2007). "Procalcitonin for the clinical laboratory: a review". Pathology. 39 (4): 383–390. S2CID 28018130.
- Grani G, Nesca A, Del Sordo M, Calvanese A, Carbotta G, Bianchini M, Fumarola A (June 2012). "Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis". Endocrine-Related Cancer. 19 (3). PMID 22399011.
External links
- The Calcitonin Protein
- Calcitonin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)