**5. References**


<sup>\*</sup> Corresponding Authors

[9] Le Douarin N, Le Lièvre C (1970). [Demonstration of neural origin of calcitonin cells of ultimobranchial body of chick embryo C R Acad Sci Hebd Seances Acad Sci D. 270:2857-60.

70 Thyroid Hormone

**4. Conclusion** 

**Author details** 

**Acknowledgement** 

**5. References** 

 \*

Corresponding Authors

In conclusion, according to the data published so far in the literature and revised through this chapter, a number of regulatory factors are produced at thyroid level by C cells and have direct effects on follicular-cell activity at both proliferative and thyroid hormone synthesis levels (Figure 9). These new paracrine regulatory mechanisms would justify, from a phylogenetic point of view, the parafollicular localization of C cells in mammals and might

open new molecular approaches for the treatment of human thyroid disease.

José María Fernández-Santos, Jesús Morillo-Bernal, Rocío García-Marín,

*Department of Cytology and Histology. School of Medicine, University of Seville, Spain* 

This work was supported by grants from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain (refs. CTS-439/2009 and P08-CVI-03598).The authors thank Mr.

[1] Ahren B (1991) Regulatory peptides in the thyroid gland -a review on their localization

[2] Eggo MC, Quiney VM, Campbell S (2003) Local factors regulating growth and function

[3] Biddinger PW, Ray M (1993) Distribution of C cells in the normal and diseased thyroid

[4] Conde E, Moreno AM, Martin-Lacave I, Fernandez A, Galera H (1992) Immunocytochemical study of the ultimobranchial tubule in Wistar rats. Anat Histol

[5] Martin-Lacave I, Conde E, Moreno A, Utrilla JC, Galera H (1992) Evidence of the occurrence of calcitonin cells in the ultimobranchial follicle of the rat postnatal thyroid.

[7] Sugiyama S (1971) The embryology of the human thyroid gland including ultimobranchial body and others related. Ergeb Anat Entwicklungsgesch. 44: 3-111. [8] Copp DH, Cockcroft DW, Kueh Y (1967) Calcitonin from ultimobranchial glands of

of human thyroid cells in vitro and in vivo. Mol Cell Endocrinol. 213: 47-58.

[6] Harach HR (1988) Solid cell nests of the thyroid. J Pathol. 155: 191-200.

José Carmelo Utrilla and Inés Martín-Lacave\*

gland. Pathol Annu. 28 Pt 1: 205-29.

dogfish and chickens. Science. 158: 924-5.

Embryol. 21: 94-100.

Acta Anat (Basel). 144: 93-6.

John Brown for the corrections of the English language.

and function. Acta Endocrinol (Copenh). 124: 225-32.

	- [25] Weiler R, Cidon S, Gershon MD, Tamir H, Hogue-Angeletti R, Winkler H (1989) Adrenal chromaffin granules and secretory granules from thyroid parafollicular cells have several common antigens. FEBS Lett. 257: 457-9.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 73

[39] Bussolati G, Pearse AG (1967) Immunofluorescent localization of calcitonin in the 'C'

[40] Kameda Y (1987) Localization of immunoreactive calcitonin gene-related peptide in

[41] Barasch JM, Tamir H, Nunez EA, Gershon MD (1987) Serotonin-storing secretory

[42] Arias J, Scopsi L, Fischer JA, Larsson LI (1989) Light- and electron-microscopical localization of calcitonin, calcitonin gene-related peptide, somatostatin and C-terminal gastrin/cholecystokinin immunoreactivities in rat thyroid. Histochemistry. 91: 265-72. [43] Cohen R, Delehaye MC, Minvielle S, Segond N, Taboulet J, Noel M, et al. (1992) CCP II: a novel calcitonin carboxy terminal peptide is expressed in normal thyroid tissue.

[44] Okada H, Capen CC, Rosol TJ (1995) Immunohistochemical demonstration of parathyroid hormone-related protein in thyroid gland of sheep. Vet Pathol. 32: 315-7. [45] Kvetnoy IM (1999) Extrapineal melatonin: location and role within diffuse

[46] Scopsi L, Pilotti S, Rilke F (1990) Immunocytochemical localization and identification of members of the pancreatic polypeptide (PP)-fold family in human thyroid C cells and

[47] Kosowicz J, Miskowiak B, Konwerska A, Tortorella C, Nussdorfer GG, Malendowicz LK (2003) Tissue distribution of pneumadin immunoreactivity in the rat. Peptides. 24:

[48] Xu L, Zhong F, Guo FF, Zhao WJ, Sun XR, Wei XF (2008) [Expression of motilin and its precursor mRNA in normal parenchyma, benign and malignant tumors of human

[49] Matsuo T, Yamaguchi H, Kageyama H, Sasaki K, Shioda S, Minamino N, et al. (2010) Localization of neuroendocrine regulatory peptide-1 and-2 in human tissues. Regul

[50] Christensen L, Johansen N, Jensen BA, Clemmensen I (1987) Immunohistochemical localization of a novel, human plasma protein, tetranectin, in human endocrine tissues.

[51] Kodama T, Fujino M, Endo Y, Obara T, Fujimoto Y, Oda T, et al. (1980) Identification of carcinoembryonic antigen in the C-cell of the normal thyroid. Cancer. 45: 98-101. [52] Braas KM, Harakall SA, Ouafik L, Eipper BA, May V (1992) Expression of peptidylglycine alpha-amidating monooxygenase: an in situ hybridization and

[53] Nishiyama I, Ogiso M, Oota T, Kimura T, Seki T (1996) Developmental change in expression of highly polysialylated neural cell adhesion molecule in C-cells in rat

[54] Darlington DN, Schiller MR, Mains RE, Eipper BA (1997) The expression of regulated endocrine-specific protein of 18 kDa in peptidergic cells of rat peripheral endocrine

cells of pig and dog thyroid. The Journal of endocrinology. 37: 205-9.

granules from thyroid parafollicular cells. J Neurosci. 7: 4017-33.

Biochem Biophys Res Commun. 185: 330-4.

neuroendocrine system. Histochem J. 31: 1-12.

medullary carcinomas. Regul Pept.30: 89-104.

thyroid]. Zhonghua Bing Li Xue Za Zhi. 37: 243-9.

immunocytochemical study. Endocrinology. 130: 2778-88.

thyroid gland. Anat Embryol (Berl). 194: 419-26.

tissues and in blood. J Endocrinol. 155: 329-41.

215-20.

Pept. 163: 43-8.

Histochemistry. 87: 195-9.

thyroid C cells from various mammalian species. Anat Rec. 219: 204-12.


[39] Bussolati G, Pearse AG (1967) Immunofluorescent localization of calcitonin in the 'C' cells of pig and dog thyroid. The Journal of endocrinology. 37: 205-9.

72 Thyroid Hormone

[25] Weiler R, Cidon S, Gershon MD, Tamir H, Hogue-Angeletti R, Winkler H (1989) Adrenal chromaffin granules and secretory granules from thyroid parafollicular cells

[26] Marcinkiewicz M, Benjannet S, Falgueyret JP, Seidah NG, Schurch W, Verdy M, et al. (1988) Identification and localization of 7B2 protein in human, porcine, and rat thyroid

[27] Schmid KW, Kunk B, Kirchmair R, Totsch M, Bocker W, Fischer-Colbrie R (1995) Immunohistochemical detection of secretoneurin, a novel neuropeptide endoproteolytically processed from secretogranin II, in normal human endocrine and

[28] Tomita T (1997) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in thyroid C-cells and medullary thyroid carcinomas. Histopathology. 31: 150-6. [29] Kurabuchi S, Tanaka S (2002) Immunocytochemical localization of prohormone convertases PC1 and PC2 in the mouse thyroid gland and respiratory tract. J Histochem

[30] Sabate MI, Stolarsky LS, Polak JM, Bloom SR, Varndell IM, Ghatei MA, et al. (1985) Regulation of neuroendocrine gene expression by alternative RNA processing. Colocalization of calcitonin and calcitonin gene-related peptide in thyroid C-cells. J Biol

[31] Ali-Rachedi A, Varndell IM, Facer P, Hillyard CJ, Craig RK, MacIntyre I, et al. (1983) Immunocytochemical localisation of katacalcin, a calcium-lowering hormone cleaved

[32] Sunday ME, Wolfe HJ, Roos BA, Chin WW, Spindel ER (1988) Gastrin-releasing peptide gene expression in developing, hyperplastic, and neoplastic human thyroid C-cells.

[33] Kameda Y, Oyama H, Endoh M, Horino M (1982) Somatostatin immunoreactive C cells

[34] Domin J, Al-Madani AM, Desperbasques M, Bishop AE, Polak JM, Bloom SR (1990) Neuromedin U-like immunoreactivity in the thyroid gland of the rat. Cell Tissue Res.

[35] Grunditz T, Persson P, Hakanson R, Absood A, Bottcher G, Rerup C, et al. (1989) Helodermin-like peptides in thyroid C cells: stimulation of thyroid hormone secretion and suppression of calcium incorporation into bone. Proc Natl Acad Sci U S A. 86: 1357-

[36] Gkonos PJ, Tavianini MA, Liu CC, Roos BA (1989) Thyrotropin-releasing hormone gene

[37] Wierup N, Kuhar M, Nilsson BO, Mulder H, Ekblad E, Sundler F (2004) Cocaine- and amphetamine-regulated transcript (CART) is expressed in several islet cell types during

[38] Raghay K, Garcia-Caballero T, Nogueiras R, Morel G, Beiras A, Dieguez C, et al. (2006) Ghrelin localization in rat and human thyroid and parathyroid glands and tumours.

expression in normal thyroid parafollicular cells. Mol Endocrinol. 3: 2101-9.

rat development. J Histochem Cytochem. 52: 169-77.

Histochem Cell Biol. 125: 239-46.

from the human calcitonin precursor. J Clin Endocrinol Metab. 57: 680-2.

in thyroid glands from various mammalian species. Anat Rec. 204: 161-70.

gland and in human medullary carcinoma. Endocrinology. 123: 866-73.

have several common antigens. FEBS Lett. 257: 457-9.

neuronal tissues. Histochem J. 27: 473-81.

Cytochem. 50: 903-9.

Chem. 260: 2589-92.

260: 131-5.

61.

Endocrinology. 122: 1551-8.

	- [55] Martin-Lacave I, Utrilla JC (2000) Expression of a neu/c-erbB-2-like product in neuroendocrine cells of mammals. Histol Histopathol. 15: 1027-33.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 75

[71] Perez Cano R, Girgis SI, MacIntyre I (1982) Further evidence for calcitonin gene duplication: the identification of two different calcitonins in a fish, a reptile and two

[72] Inzerillo AM, Zaidi M, Huang CL (2002) Calcitonin: the other thyroid hormone.

[73] Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different

[74] Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, et al. (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-

[75] Fischer JA, Tobler PH, Henke H, Tschopp FA (1983) Salmon and human calcitonin-like peptides coexist in the human thyroid and brain. J Clin Endocrinol Metab. 57: 1314-6. [76] Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A, et al. (1991) Expression cloning of an adenylate cyclase-coupled calcitonin receptor. Science. 254: 1022-4. [77] Pondel MD, Jagger C, Hebden C, Partington G, Mould R (2002) Transcriptional

[78] Gorn AH, Rudolph SM, Flannery MR, Morton CC, Weremowicz S, Wang TZ, et al. (1995) Expression of two human skeletal calcitonin receptor isoforms cloned from a giant cell tumor of bone. The first intracellular domain modulates ligand binding and

[79] Frendo JL, Delage-Mourroux R, Cohen R, Pichaud F, Pidoux E, Guliana JM, et al. (1998) Calcitonin receptor mRNA is expressed in human medullary thyroid carcinoma.

[80] Breimer LH, MacIntyre I, Zaidi M (1988) Peptides from the calcitonin genes: molecular

[81] Seifert H, Sawchenko P, Chesnut J, Rivier J, Vale W, Pandol SJ (1985) Receptor for calcitonin gene-related peptide: binding to exocrine pancreas mediates biological

[82] Zaidi M, Chambers TJ, Bevis PJ, Beacham JL, Gaines Das RE, MacIntyre I (1988) Effects of peptides from the calcitonin genes on bone and bone cells. Q J Exp Physiol. 73: 471-

[83] Ahren B (1989) Effects of calcitonin, katacalcin, and calcitonin gene-related peptide on basal and TSH-stimulated thyroid hormone secretion in the mouse. Acta Physiol Scand.

[84] Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, et al. (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone.

[85] Patel YC (1999) Somatostatin and its receptor family. Front Neuroendocrinol. 20: 157-98.

[88] Epelbaum J, Dournaud P, Fodor M, Viollet C (1994) The neurobiology of somatostatin.

[87] Reichlin S (1983) Somatostatin (second of two parts). N Engl J Med. 309: 1556-63.

regulation of the calcitonin receptor gene. Biochem Soc Trans. 30: 423-7.

mammals. Acta Endocrinol (Copenh). 100: 256-61.

polypeptide products. Nature. 298: 240-4.

specific RNA processing. Nature. 304: 129-35.

signal transduction. J Clin Invest. 95: 2680-91.

actions. Am J Physiol. 249: G147-51.

genetics, structure and function. Biochem J. 255: 377-90.

[86] Reichlin S (1983) Somatostatin. N Engl J Med. 309: 1495-501.

Thyroid. 12: 791-8.

Thyroid. 8: 141-7.

85.

135: 133-7.

Science. 179: 77-9.

Crit Rev Neurobiol. 8: 25-44.


[71] Perez Cano R, Girgis SI, MacIntyre I (1982) Further evidence for calcitonin gene duplication: the identification of two different calcitonins in a fish, a reptile and two mammals. Acta Endocrinol (Copenh). 100: 256-61.

74 Thyroid Hormone

Histochem. 97: 389-99.

Pathol. 4: 297-304.

Metab Res. 25: 473-6.

150-8.

81: 405-22.

genes. J Endocrinol. 92: 351-5.

changes in rats. J Anat. 214: 301-9.

[55] Martin-Lacave I, Utrilla JC (2000) Expression of a neu/c-erbB-2-like product in

[56] Sawicki B (1995) Evaluation of the role of mammalian thyroid parafollicular cells. Acta

[57] Ahren B (1989) Effects of gastrin-releasing peptide on basal and stimulated thyroid

[58] Tamir H, Hsiung SC, Yu PY, Liu KP, Adlersberg M, Nunez EA, et al. (1992) Serotonergic signalling between thyroid cells: protein kinase C and 5-HT2 receptors in

[59] Forssell-Aronsson EB, Nilsson O, Bejegard SA, Kolby L, Bernhardt P, Molne J, et al. (2000) 111In-DTPA-D-Phe1-octreotide binding and somatostatin receptor subtypes in

[60] De Miguel M, Fernandez-Santos JM, Utrilla JC, Carrillo-Vico A, Borrero J, Conde E, et al. (2005) Thyrotropin-releasing hormone receptor expression in thyroid follicular cells:

[61] Albores-Saavedra J, Monforte H, Nadji M, Morales AR (1988) C-cell hyperplasia in

[62] Scopsi L, Di Palma S, Ferrari C, Holst JJ, Rehfeld JF, Rilke F (1991) C-cell hyperplasia accompanying thyroid diseases other than medullary carcinoma: an immunocytochemical study by means of antibodies to calcitonin and somatostatin. Mod

[63] Martin-Lacave I, Borrero MJ, Utrilla JC, Fernandez-Santos JM, de Miguel M, Morillo J, et al. (2009) C cells evolve at the same rhythm as follicular cells when thyroidal status

[64] Morillo-Bernal J, Fernandez-Santos JM, Utrilla JC, de Miguel M, Garcia-Marin R, Martin-Lacave I (2009) Functional expression of the thyrotropin receptor in C cells: new insights into their involvement in the hypothalamic-pituitary-thyroid axis. J Anat. 215:

[65] Raue F, Zink A, Scherubl H (1993) Regulation of calcitonin secretion in vitro. Horm

[66] Suzuki K, Lavaroni S, Mori A, Okajima F, Kimura S, Katoh R, et al. (1998) Thyroid transcription factor 1 is calcium modulated and coordinately regulates genes involved

[67] Copp DH, Cameron EC (1961) Demonstration of a hypocalcemic factor (calcitonin) in

[68] Kumar MA, Foster GV, MacIntyre I (1963) Further Evidence for Calcitonin. A Rapid-

[69] Pondel M (2000) Calcitonin and calcitonin receptors: bone and beyond. Int J Exp Pathol.

[70] Perez Cano R, Girgis SI, Galan Galan F, MacIntyre I (1982) Identification of both human and salmon calcitonin-like molecules in birds suggesting the existence of two calcitonin

neuroendocrine cells of mammals. Histol Histopathol. 15: 1027-33.

hormone secretion in the mouse. Acta Endocrinol (Copenh). 120: 245-9.

the secretion and action of serotonin. Synapse. 12: 155-68.

a new paracrine role of C-cells? Histol Histopathol. 20: 713-8.

in calcium homeostasis in C cells. Mol Cell Biol. 18: 7410-22.

Acting Hormone Which Lowers Plasma-Calcium. Lancet. 2: 480-2.

commercial parathyroid extract. Science. 134: 2038.

thyroid tissue adjacent to follicular cell tumors. Hum Pathol. 19: 795-9.

thyroid tumors. J Nucl Med. 41: 636-42.


[89] Aguila MC, Rodriguez AM, Aguila-Mansilla HN, Lee WT (1996) Somatostatin antisense oligodeoxynucleotide-mediated stimulation of lymphocyte proliferation in culture. Endocrinology. 137: 1585-90.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 77

[106] de la Pena P, Delgado LM, del Camino D, Barros F (1992) Two isoforms of the thyrotropin-releasing hormone receptor generated by alternative splicing have

[107] O'Dowd BF, Lee DK, Huang W, Nguyen T, Cheng R, Liu Y, et al. (2000) TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic

[108] Cao J, O'Donnell D, Vu H, Payza K, Pou C, Godbout C, et al. (1998) Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing

[109] Deflorian F, Engel S, Colson AO, Raaka BM, Gershengorn MC, Costanzi S (2008) Understanding the structural and functional differences between mouse thyrotropin-

[110] Griffiths EC (1985) Thyrotrophin releasing hormone: endocrine and central effects.

[111] Sun Y, Zupan B, Raaka BM, Toth M, Gershengorn MC (2009) TRH-receptor-type-2 deficient mice are euthyroid and exhibit increased depression and reduced anxiety

[112] Satoh T, Feng P, Kim UJ, Wilber JF (1994) Identification of thyrotropin-releasing

[113] Mellado M, Fernandez-Agullo T, Rodriguez-Frade JM, San Frutos MG, de la Pena P, Martinez AC, et al. (1999) Expression analysis of the thyrotropin-releasing hormone receptor (TRHR) in the immune system using agonist anti-TRHR monoclonal

[114] Morley JE (1979) Extrahypothalamic thyrotropin releasing hormone (TRH) -- its

[115] Pekary AE, Reeve JR, Jr., Smith VP (1986) Evidence for thyrotropin-releasing hormone

[116] Iversen E, Weeke J, Laurberg P (1984) TRH immunoreactivity in the thyroid gland.

[117] Montagne JJ, Ladram A, Grouselle D, Nicolas P, Bulant M (1997) Thyrotropinreleasing hormone immunoreactivity in rat adrenal tissue is localized in mast cells. J

[118] Bacova Z, Baqi L, Benacka O, Payer J, Krizanova O, Zeman M, et al. (2006) Thyrotropin-releasing hormone in rat heart: effect of swelling, angiotensin II and renin

[119] Yamada M, Shibusawa N, Ishii S, Horiguchi K, Umezawa R, Hashimoto K, et al. (2006) Prolactin secretion in mice with thyrotropin-releasing hormone deficiency.

[120] Delbeke D, Van Sande J, Cochaux P, Decoster C, Dumont JE (1983) Effect of thyrotropin-releasing hormone on dog thyroid in vitro. Biochim Biophys Acta. 761: 262-

[121] Iversen E, Laurberg P (1985) Thyrotrophin-releasing hormone (TRH) and hormone secretion from the follicular and C-cells of perfused dog thyroid lobes. Acta Endocrinol

indistinguishable functional properties. J Biol Chem. 267: 25703-8.

distribution compared with TRH-R1. Mol Endocrinol. 14: 183-93.

releasing hormone receptors 1 and 2. Proteins. 71: 783-94.

phenotypes. Neuropsychopharmacology. 34: 1601-8.

distribution and its functions. Life Sci. 25: 1539-50.

(TRH) biosynthesis in rat prostate. Life Sci. 39: 2565-70.

hormone receptor in the rat testis. Neuropeptides. 27: 195-202.

hormone receptor. J Biol Chem. 273: 32281-7.

Psychoneuroendocrinology. 10: 225-35.

antibodies. FEBS Lett. 451: 308-14.

Scand J Clin Lab Invest. 44: 703-9.

Histochem Cytochem. 45: 1623-7.

gene. Acta Physiol (Oxf). 187: 313-9.

Endocrinology. 147: 2591-6.

(Copenh). 109: 499-504.

8.


[106] de la Pena P, Delgado LM, del Camino D, Barros F (1992) Two isoforms of the thyrotropin-releasing hormone receptor generated by alternative splicing have indistinguishable functional properties. J Biol Chem. 267: 25703-8.

76 Thyroid Hormone

405.

Endocrinology. 137: 1585-90.

[89] Aguila MC, Rodriguez AM, Aguila-Mansilla HN, Lee WT (1996) Somatostatin antisense oligodeoxynucleotide-mediated stimulation of lymphocyte proliferation in culture.

[90] Karalis K, Mastorakos G, Chrousos GP, Tolis G (1994) Somatostatin analogues suppress

[91] Elliott DE, Blum AM, Li J, Metwali A, Weinstock JV (1998) Preprosomatostatin messenger RNA is expressed by inflammatory cells and induced by inflammatory

[92] Patel YC, Srikant CB (1997) Somatostatin receptors. Trends Endocrinol Metab. 8: 398-

[93] Raynor K, Coy DC, Reisine T (1992) Analogues of somatostatin bind selectively to brain

[94] Reisine T, Woulfe D, Raynor K, Kong H, Heerding J, Hines J, et al. (1995) Interaction of somatostatin receptors with G proteins and cellular effector systems. Ciba Foundation

[95] Van Noorden S, Polak JM, Pearse AG (1977) Single cellular origin of somatostatin and

[96] Alumets J, Hakanson R, Lundqvist G, Sundler F, Thorell J (1980) Ontogeny and ultrastructure of somatostatin and calcitonin cells in the thyroid gland of the rat. Cell

[97] Zabel M, Surdyk J, Biela-Jacek I (1987) Immunocytochemical studies on thyroid parafollicular cells in postnatal development of the rat. Acta Anat (Basel). 130: 251-6. [98] Fierabracci A, Castagna M, Baschieri L (1993) Calcitonin and somatostatin containing C cells in rat and human thyroid. Immunohistochemical study by a double-staining

[99] Ahren B, Hedner P, Melander A, Westgren U (1977) Inhibition by somatostatin of mouse thyroid activity following stimulation by thyrotrophin, isoprenaline and

[100] Loos U, Raptis S, Birk J, Escobar-Jimenez F, Meyer G, Rothenbuchner G, et al. (1978) Inhibition of TSH-stimulated radioiodine turnover and release of T4 and T3 in vivo by

[101] Siperstein AE, Levin KE, Gum ET, Clark OH (1992) Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue. World J Surg. 16: 555-60. [102] Brandi ML, Toccafondi R (1985) Neuropeptidergic control of cyclic AMP accumulation

[103] degli Uberti EC, Hanau S, Rossi R, Piva R, Margutti A, Trasforini G, et al. (1991) Somatostatin reduces 3H-thymidine incorporation and c-myc, but not thyroglobulin ribonucleic acid levels in human thyroid follicular cells in vitro. J Clin Endocrinol

[104] Lechan RM, Wu P, Jackson IM (1986) Immunolocalization of the thyrotropin-releasing hormone prohormone in the rat central nervous system. Endocrinology. 119: 1210-6. [105] Lechan RM, Wu P, Jackson IM, Wolf H, Cooperman S, Mandel G, et al. (1986) Thyrotropin-releasing hormone precursor: characterization in rat brain. Science. 231:

the inflammatory reaction in vivo. J Clin Invest. 93: 2000-6.

somatostatin receptor subtypes. J Neurochem. 59: 1241-50.

calcitonin in the rat thyroid gland. Histochemistry. 53: 243-7.

dibutyryl cyclic-AMP Acta Endocrinol (Copenh). 86: 323-9.

mediators and cytokines. J Immunol. 160: 3997-4003.

symposium. 190: 160-7; discussion 7-70.

Tissue Res. 206: 193-201.

method. Pathologica. 85: 467-74.

somatostatin. Metabolism. 27: 1269-73.

in human thyroid cell. Peptides. 6: 641-4.

Metab. 72: 1364-71.

159-61.


[122] Rausell V, Fraser HM, Tobaruela M, del Rio-Garcia J, Smyth DG (1999) Identification of the TRH-like peptides pGlu-Glu-Pro amide and pGlu-Phe-Pro amide in rat thyroid: regulation by thyroid status. Reg Pept. 81: 55-60.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 79

[137] Katergari SA, Milousis A, Pagonopoulou O, Asimakopoulos B, Nikolettos NK (2008)

[138] Kanamoto N, Akamizu T, Hosoda H, Hataya Y, Ariyasu H, Takaya K, et al. (2001) Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. J

[139] Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in

[140] Volante M, Allia E, Fulcheri E, Cassoni P, Ghigo E, Muccioli G, et al. (2003) Ghrelin in fetal thyroid and follicular tumors and cell lines: expression and effects on tumor

[141] Park YJ, Lee YJ, Kim SH, Joung DS, Kim BJ, So I, et al. (2008) Ghrelin enhances the proliferating effect of thyroid stimulating hormone in FRTL-5 thyroid cells. Mol Cell

[142] Riesco-Eizaguirre G, Santisteban P (2006) A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 155: 495-512. [143] Ueberberg B, Unger N, Saeger W, Mann K, Petersenn S (2009) Expression of ghrelin

[144] Kluge M, Riedl S, Uhr M, Schmidt D, Zhang X, Yassouridis A, et al. (2010) Ghrelin affects the hypothalamus-pituitary-thyroid axis in humans by increasing free thyroxine

[145] Sosic-Jurjevic B, Stevanovic D, Milosevic V, Sekulic M, Starcevic V (2009) Central ghrelin affects pituitary-thyroid axis: histomorphological and hormonal study in rats.

[146] Spiess J, Villarreal J, Vale W (1981) Isolation and sequence analysis of a somatostatin-

[147] Douglass J, McKinzie AA, Couceyro P (1995) PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J

[148] Kuhar MJ, Adams LD, Hunter RG, Vechia SD, Smith Y (2000) CART peptides. Reg

[149] Broberger C (1999) Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y. Brain Res. 848:

[150] Couceyro P, Paquet M, Koylu E, Kuhar MJ, Smith Y (1998) Cocaine- and amphetamine-regulated transcript (CART) peptide immunoreactivity in myenteric plexus neurons of the rat ileum and co-localization with choline acetyltransferase.

[151] Koylu EO, Couceyro PR, Lambert PD, Kuhar MJ (1998) Cocaine- and amphetamineregulated transcript peptide immunohistochemical localization in the rat brain. J Comp

[152] Smith Y, Kieval J, Couceyro PR, Kuhar MJ (1999) CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys: ultrastructural analysis, colocalization

and its receptor in human tissues. Horm Metab Res. 41: 814-21.

and decreasing TSH in plasma. Eur J Endocrinol. 162: 1059-65.

like polypeptide from ovine hypothalamus. Biochemistry. 20: 1982-8.

Ghrelin in pathological conditions. Endocr J. 55: 439-53.

Clin Endocrinol Metab. 86: 4984-90.

growth. Am J Pathol. 162: 645-54.

Neuroendocrinology. 89: 327-36.

Neurosci. 15: 2471-81.

Pept. 89: 1-6.

Synapse. 30: 1-8.

Neurol. 391: 115-32.

101-13.

Endocrinol. 285: 19-25.

humans. J Clin Endocrinol Metab. 87: 2988.


[137] Katergari SA, Milousis A, Pagonopoulou O, Asimakopoulos B, Nikolettos NK (2008) Ghrelin in pathological conditions. Endocr J. 55: 439-53.

78 Thyroid Hormone

[122] Rausell V, Fraser HM, Tobaruela M, del Rio-Garcia J, Smyth DG (1999) Identification of the TRH-like peptides pGlu-Glu-Pro amide and pGlu-Phe-Pro amide in rat thyroid:

[123] Raspe E, Laurent E, Andry G, Dumont JE (1991) ATP, bradykinin, TRH and TSH activate the Ca(2+)-phosphatidylinositol cascade of human thyrocytes in primary

[124] Sato A, Yamada T, Aizawa T, Ichikawa K, Komiya I, Takasu N, et al. (1995) Effect of thyrotropin-releasing hormone on serum thyroid hormones: a study in the patients with untreated and treated Graves' disease and subacute thyroiditis. J Clin Endocrinol

[125] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402: 656-60. [126] Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, et al. (2001) Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-

[127] Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB (2004) Ghrelin--a hormone

[128] Van der Lely AJ, Tschop M, Heiman ML, Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev. 25: 426-57. [129] Caminos JE, Tena-Sempere M, Gaytan F, Sanchez-Criado JE, Barreiro ML, Nogueiras R, et al. (2003) Expression of ghrelin in the cyclic and pregnant rat ovary.

[130] Fernandez-Fernandez R, Tena-Sempere M, Aguilar E, Pinilla L (2004) Ghrelin effects on gonadotropin secretion in male and female rats. Neurosci Lett. 362: 103-7. [131] Kluge M, Schussler P, Uhr M, Yassouridis A, Steiger A (2007) Ghrelin suppresses secretion of luteinizing hormone in humans. J Clin Endocrinol Metab. 92: 3202-5. [132] Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, et al. (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology.

[133] Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.

[134] Bagnasco M, Kalra PS, Kalra SP (2002) Ghrelin and leptin pulse discharge in fed and

[135] Raghay K, Garcia-Caballero T, Bravo S, Alvarez CV, Gonzalez R, Dieguez C, et al. (2008) Ghrelin localization in the medulla of rat and human adrenal gland and in

[136] Morillo-Bernal J, Fernandez-Santos JM, De Miguel M, Garcia-Marin R, Gordillo-Martinez F, Diaz-Parrado E, et al. (2011) Ghrelin potentiates TSH-induced expression of the thyroid tissue-specific genes thyroglobulin, thyroperoxidase and sodium-iodine

regulation by thyroid status. Reg Pept. 81: 55-60.

releasing hormone. J Clin Endocrinol Metab. 86: 1169-74.

with multiple functions. Front Neuroendocrinol. 25: 27-68.

culture. Mol Cell Endocrinol. 81: 175-83.

Metab. 80: 2173-7.

Endocrinology. 144: 1594-602.

141: 4255-61.

Diabetes. 50: 1714-9.

fasted rats. Endocrinology. 143: 726-9.

pheochromocytomas. Histol Histopathol. 23: 57-65.

symporter, in rat PC-Cl3 Cells. Peptides. 32:2333-9


studies, and synaptic interactions with dopaminergic afferents. J Comp Neurol. 407: 491-511.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 81

[167] Ganguly S, Coon SL, Klein DC (2002) Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation. Cell Tissue Res. 309:

[168] Cooper R, Lerer B (2010) [The use of thyroid hormones in the treatment of depression].

[169] Catini C, Legnaioli M (1992) Role of mast cells in health: daily rhythmic variations in their number, exocytotic activity, histamine and serotonin content in the rat thyroid

[170] Melander A, Sundler F (1972) Significance of thyroid mast cells in thyroid hormone

[171] Melander A, Westgren U, Sundler F, Ericson LE (1975) Influence of histamine- and 5 hydroxytryptamine-containing thyroid mast cells on thyroid blood flow and

[172] Tamir H, Hsiung SC, Liu KP, Blakely RD, Russo AF, Clark MS, et al. (1996) Expression and development of a functional plasmalemmal 5-hydroxytryptamine transporter by

[173] Falck B, Owman C (1968) 5-hydroxytryptamine and related amines in endocrine cell

[174] Machado CR (1976) Monoamines in the C cells of the thyroid gland of callithricid

[175] Nunez EA, Gershon MD (1972) Synthesis and storage of serotonin by parafollicular (C) cells of the thyroid gland of active, prehibernating and hibernating bats.

[176] Zabel M (1984) Ultrastructural localization of calcitonin, somatostatin and serotonin in

[177] Bernd P, Gershon MD, Nunez EA, Tamir H (1981) Separation of dissociated thyroid follicular and parafollicular cells: association of serotonin binding protein with

[178] Tamir H, Liu KP, Hsiung SC, Adlersberg M, Nunez EA, Gershon MD (1990) Multiple signal transduction mechanisms leading to the secretion of 5-hydroxytryptamine by

[179] Tamir H, Liu KP, Payette RF, Hsiung SC, Adlersberg M, Nunez EA, et al. (1989) Human medullary thyroid carcinoma: characterization of the serotonergic and neuronal

[180] Solcia E, Sampietro R (1968) New methods for staining secretory granules and 5 hydroxytryptamine in the thyroid C-cells. In: Taylor S, Editor. Calcitonin: Proceedings of the symposium on thyrocalcitonin and the C cells. New York: Springer-Verlag. p.

[181] Liu KP, Russo AF, Hsiung SC, Adlersberg M, Franke TF, Gershon MD, et al. (2003) Calcium receptor-induced serotonin secretion by parafollicular cells: role of phosphatidylinositol 3-kinase-dependent signal transduction pathways. J Neurosci. 23:

[182] Reiter RJ (1993) The melatonin rhythm: both a clock and a calendar. Experientia. 49:

MTC cells, a neurectodermally derived cell line. J Neurosci. 10: 3743-53.

properties of a neurectodermally derived cell line. J Neurosci. 9: 1199-212.

127-37.

Harefuah. 149: 529-34, 50, 49.

gland. Eur J Histochem. 36: 501-16.

secretion. Endocrinology. 90: 802-7.

systems. Adv Pharmacol. 6: 211-31.

primates. Histochemistry. 48: 187-90.

parafollicular cells. J Cell Biol. 88: 499-508.

Endocrinology. 90: 1008-24.

127-32.

2049-57.

654-64.

permeability in the rat. Endocrinology. 97: 1130-7.

thyroid follicular cells. Endocrinology. 137: 4475-86.

parafollicular cells of rat thyroid. Histochem J. 16: 1265-72.


[167] Ganguly S, Coon SL, Klein DC (2002) Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation. Cell Tissue Res. 309: 127-37.

80 Thyroid Hormone

491-511.

Endocrinol. 4: 22.

thyroid glands. BMC Neurosci. 8: 51.

central amygdale. J Neurosci. 30: 5713-23.

behaviour. Brain research. 818: 499-509.

receptors. Neuroscience letters. 384: 198-202.

studies, and synaptic interactions with dopaminergic afferents. J Comp Neurol. 407:

[153] Koylu EO, Couceyro PR, Lambert PD, Ling NC, DeSouza EB, Kuhar MJ (1997) Immunohistochemical localization of novel CART peptides in rat hypothalamus,

[154] Kobayashi Y, Jimenez-Krassel F, Ireland JJ, Smith GW (2006) Evidence of a local negative role for cocaine and amphetamine regulated transcript (CART), inhibins and low molecular weight insulin like growth factor binding proteins in regulation of granulosa cell estradiol production during follicular waves in cattle. Reprod Biol

[155] Wierup N, Gunnarsdottir A, Ekblad E, Sundler F (2007) Characterisation of CARTcontaining neurons and cells in the porcine pancreas, gastro-intestinal tract, adrenal and

[156] Hunter RG, Philpot K, Vicentic A, Dominguez G, Hubert GW, Kuhar MJ (2004) CART in feeding and obesity. Trends in endocrinology and metabolism: TEM. 15: 454-9. [157] Leshan RL, Opland DM, Louis GW, Leinninger GM, Patterson CM, Rhodes CJ, et al. (2010) Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended

[158] Koylu EO, Balkan B, Kuhar MJ, Pogun S (2006) Cocaine and amphetamine regulated

[159] Vrang N, Tang-Christensen M, Larsen PJ, Kristensen P (1999) Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding

[160] Lakatos A, Prinster S, Vicentic A, Hall RA, Kuhar MJ (2005) Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signalregulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled

[161] Fekete C, Lechan RM (2006) Neuroendocrine implications for the association between cocaine- and amphetamine regulated transcript (CART) and hypophysiotropic

[162] Lopez M, Seoane L, Tovar S, Senaris RM, Dieguez C (2002) Thyroid status regulates CART but not AgRP mRNA levels in the rat hypothalamus. Neuroreport. 13: 1775-9. [163] Fekete C, Mihaly E, Luo LG, Kelly J, Clausen JT, Mao Q, et al. (2000) Association of cocaine- and amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-

[164] Rapport MM, Green AA, Page IH (1948) Serum vasoconstrictor, serotonin; isolation

[165] Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annu Rev

[166] Giarman NJ, Freedman DX (1960) Serotonin content of the pineal glands of man and

transcript (CART) and the stress response. Peptides. 27: 1956-69.

thyrotropin-releasing hormone (TRH). Peptides. 27: 2012-8.

thyroid axis during fasting J Neurosci. 20: 9224-34.

and characterization. J Biol Chem. 176: 1243-51.

Med. 60: 355-66.

monkey. Nature. 186: 480-1.

pituitary and adrenal gland. J Neuroendocrinol. 9: 823-33.


[183] Lerner AB, Case JD, Takahashi Y (1958) Isolation of melatonin, pineal factor that lightens melanocytes. J Am Chem Soc. *80*: 2057-8.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells 83

[201] Djeridane Y, Vivien-Roels B, Simonneaux V, Miguez JM, Pevet P (1998) Evidence for melatonin synthesis in rodent Harderian gland: a dynamic in vitro study. J Pineal Res.

[202] Konturek SJ, Konturek PC, Brzozowska I, Pawlik M, Sliwowski Z, Czesnikiewicz-Guzik M, et al. (2007) Localization and biological activities of melatonin in intact and

[203] Itoh MT, Ishizuka B, Kudo Y, Fusama S, Amemiya A, Sumi Y (1997) Detection of melatonin and serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase

[204] Itoh MT, Ishizuka B, Kuribayashi Y, Amemiya A, Sumi Y (1999) Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod.

[205] Carrillo-Vico A CJ, Abreu P, Lardone PJ, García-Mauriño S, Reiter RJ, Guerrero JM. (2004) Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J.

[206] Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, Carrascosa-Salmoral MP, et al. (2007) Melatonin biosynthesis in the thymus of humans and rats. Cell Mol

[207] Fischer T.W. SA, Zmijewski M.A., Reiter R.J. and Paus R (2008) Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair. Exp Dermatol. 9:

[208] Tijmes M, Pedraza R, Valladares L (1996) Melatonin in the rat testis: evidence for local

[209] Garcia-Marin R, De Miguel M, Fernandez-Santos JM, A. C-V, Utrilla JC, Morillo-Bernal J, et al. (2012) Melatonin-Synthesizing Enzimes and Melatonin Receptors in rat Thyroid

[210] Lewinski A, Sewerynek E (1986) Melatonin inhibits the basal and TSH-stimulated mitotic activity of thyroid follicular cells in vivo and in organ culture. J Pineal Res. 3: 291-9. [211] Wright ML, Pikula A, Babski AM, Labieniec KE, Molan RB (1996) Effect of Melatonin on the Response of the Thyroid to Thyrotropin Stimulation in Vitro. Gen Comp

[212] Makay B, Makay O, Yenisey C, Icoz G, Ozgen G, Unsal E, et al. (2009) The interaction of oxidative stress response with cytokines in the thyrotoxic rat: is there a link?

[213] Karbownik M, Lewinski A (2003) Melatonin reduces Fenton reaction-induced lipid

[214] Rao MV, Chhunchha B (2010) Protective role of melatonin against the mercury

[215] Tan DX, Manchester LC, Reiter RJ, Plummer BF, Limson J, Weintraub ST, et al. (2000) Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway

[216] Sainz RM, Mayo JC, Reiter RJ, Tan DX, Rodriguez C (2003) Apoptosis in primary

peroxidation in porcine thyroid tissue. J Cell Biochem 90: 806-11.

of melatonin biotransformation. Free Radic Biol Med. 29: 1177-85.

lymphoid organs with aging. Microsc Res Tech. 62: 524-39.

induced oxidative stress in the rat thyroid. Food Chem Toxicol. 48: 7-10.

diseased gastrointestinal tract (GIT). J Physiol Pharmacol. 58: 381-405.

activities in rat ovary. Mol Cell Endocrinol. 136: 7-13.

25: 54-64.

5: 402-8.

18: 537-9.

713-30.

Life Sci. 64: 781-90.

synthesis. Steroids. 61: 65-8.

Endocrinol. 108: 298-305.

Mediators Inflamm. 2009: 391682.

Cells. Histol Histopathol. Paper in press.


[201] Djeridane Y, Vivien-Roels B, Simonneaux V, Miguez JM, Pevet P (1998) Evidence for melatonin synthesis in rodent Harderian gland: a dynamic in vitro study. J Pineal Res. 25: 54-64.

82 Thyroid Hormone

29: 119-23.

10913-8.

420-9.

2183-98.

59: 37-47.

melatonin. Science. 131: 1312.

Chronobiol Int. 19: 649-58.

[183] Lerner AB, Case JD, Takahashi Y (1958) Isolation of melatonin, pineal factor that

[184] Hardeland R, Fuhrberg B, Uria H, Behrmann G, Meyer TJ, Burkhardt S, et al. (1996) Chronobiology of indoleamines in the dinoflagellate Gonyaulax polyedra: metabolism and effects related to circadian rhythmicity and photoperiodism. Braz J Med Biol Res.

[185] Hardeland R, Poeggeler B (2003) Non-vertebrate melatonin. J Pineal Res. 34: 233-41. [186] Voisin P, Namboodiri MA, Klein DC (1984) Arylamine N-acetyltransferase and arylalkylamine N-acetyltransferase in the mammalian pineal gland. J Biol Chem. 259:

[187] Axelrod J, Weissbach H (1960) Enzymatic O-methylation of N-acetylserotonin to

[188] Redman J, Armstrong S, Ng KT (1983) Free-running activity rhythms in the rat:

[189] Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA (2002) Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period.

[190] Hack LM, Lockley SW, Arendt J, Skene DJ (2003) The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms. 18:

[191] Sharkey KM, Fogg LF, Eastman CL (2002) Effects of melatonin administration on

[192] Reiter RJ, Tan DX, Maldonado MD (2005) Melatonin as an antioxidant: physiology

[193] Mogulkoc R, Baltaci AK, Oztekin E, Aydin L, Sivrikaya A (2006) Melatonin prevents oxidant damage in various tissues of rats with hyperthyroidism. Life Sci. 79: 311-5. [194] Lewinski A, Karbownik M (2002) Review. Melatonin and the thyroid gland. Neuro

[195] Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA (2003) Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci. 72:

[196] Pang SF, Dubocovich ML, Brown GM (1993) Melatonin receptors in peripheral tissues:

[197] Ishii H, Tanaka N, Kobayashi M, Kato M, Sakuma Y (2009) Gene structures, biochemical characterization and distribution of rat melatonin receptors. J Physiol Sci.

[198] Rafii-El-Idrissi M CJ, Harmouch A, García-Mauriño S, Guerrero JM. (1998) Specific binding of melatonin by purified cell nuclei from spleen and thymus of the rat. J

[199] Smirnov AN (2001) Nuclear melatonin receptors. Biochemistry (Mosc). 66: 19-26. [200] Iuvone PM, Brown AD, Haque R, Weller J, Zawilska JB, Chaurasia SS, et al. (2002) Retinal melatonin production: role of proteasomal proteolysis in circadian and photic control of arylalkylamine N-acetyltransferase. Invest Ophthalmol Vis Sci. 43: 564-72.

daytime sleep after simulated night shift work. J Sleep Res 10: 181-92.

lightens melanocytes. J Am Chem Soc. *80*: 2057-8.

entrainment by melatonin. Science. 219: 1089-91.

versus pharmacology. J Pineal Res. 39: 215-6.

a new area of melatonin research. Biol Signals. 2: 177-80.

Endocrinol Lett. 23 Suppl 1: 73-8.

Neuroimmunol. 86: 190-7.


[217] Kameya T, Bessho T, Tsumuraya M, Yamaguchi K, Abe K, Shimosato Y, et al. (1983) Production of gastrin releasing peptide by medullary carcinoma of the thyroid. An immunohistochemical study. Virchows Arch A Pathol Anat Histopathol. 401: 99-107.

**Chapter 4** 

© 2012 Dietzel et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Since many of the neurological symptoms observed in hypothyroidism point to a conspicuous mental slowing as leading symptom of hypothyroidism, we here were

and reproduction in any medium, provided the original work is properly cited.

**Thyroid Hormone Effects on Sensory** 

**Perception, Mental Speed, Neuronal** 

Additional information is available at the end of the chapter

these symptoms is still a matter of debate (35).

and Katharina Bohr

http://dx.doi.org/10.5772/48310

**1. Introduction** 

**Excitability and Ion Channel Regulation** 

Irmgard D. Dietzel, Sivaraj Mohanasundaram, Vanessa Niederkinkhaus, Gerd Hoffmann, Jens W. Meyer, Christoph Reiners, Christiana Blasl

Although thyroid hormone effects on the brain are most prominent in development, also in adult-acquired hypothyroidism symptoms such as sensory impairments, disagreeable smells and taste, slowness of thought and action, changes of speech, irritability, headaches, sleep disturbances, confusion up to delusions and hallucinations, impairments of memory, of vision as well as of hearing frequently occur. This involvement of the nervous system was already discussed in the first reports on myxoedema (1–3) and a systematic description included in the first extensive investigation by the Committee of the Clinical Society of London (4). Many of these symptoms have since been studied in considerable detail. The conspicuous slowing of movements of hypothyroid subjects has been shown to correlate with peripheral sensory and motor nerve dysfunctions and abnormal neuromuscular transmission (5–10). The slowing of thoughts and mental function occurs concomitant with a decrease in the frequency of the alpha rhythm of the EEG (11–15). In addition to the slowing of the alpha-rhythm increased latencies of visual, auditory and somatosensory evoked potentials in adult-onset hypothyroidism indicate a slowed conduction of information in the central nervous system (16–24). In addition to a slowing of neuronal conduction velocity, changes in the threshold of hearing (25–29) and of the sensation of smell have been reported (30, 31). Cognitive and memory tests revealed impaired performances, which could at least partially be reversed by hormone substitution (24, 32–34). The extent of the reversibility of

