1. bookVolume 51 (2017): Issue 2 (April 2017)
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year
access type Open Access

The role of thyrostimulin and its potential clinical significance

Published Online: 13 Jun 2017
Volume & Issue: Volume 51 (2017) - Issue 2 (April 2017)
Page range: 117 - 128
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year

Thyrostimulin is a glycoprotein heterodimer of GPA2 and GPB5, first described in 2002. It is involved in the physiological function of several tissues. Moreover, evidence points towards the ability of thyrostimulin’s individual monomers to induce a biological effect, which could denote the circulatory/systemic effects of the molecule when found in higher concentrations. From the evolutionary point of view, thyrostimulin shares a binding epitope with the thyroid-stimulating hormone for the thyroid stimulating hormone receptor, whilst possessing affinity for another unique binding site on the same receptor. Although thyrostimulin can be involved in the hypothalamicpituitary- thyroid axis, its presence in various tissues in an eclectic array of different species renders it multifunctional. From weight loss via increasing metabolic rate to progression of cancer in human ovaries, it is certainly not a signaling molecule to overlook. Furthermore, thyrostimulin has been implicated in bone metabolism, acute illness, and reproductive function. In summary, to our knowledge, this is the first review dealing with the physiological role of thyrostimulin and its potential applications in the clinical practice.


Alvarez E, Cahoreau C, Combarnous Y. Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules. Reprod Biol Endocrinol 7, 90, 2009.10.1186/1477-7827-7-90322496519715619Search in Google Scholar

Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC. Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22, 255-288, 2001.10.1210/edrv.22.2.042211294827Search in Google Scholar

Bassett JH, van der Spek A, Logan JG, Gogakos A, Bagchi-Chakraborty J, Murphy E, van Zeijl C, Down J, Croucher PI, Boyde A, Boelen A, Williams GR. Th yrostimulin regulates osteoblastic bone formation during early skeletal development. Endocrinology 156, 3098-3113, 2015.10.1210/en.2014-1943454161626018249Search in Google Scholar

Belghazi M, Klett D, Cahoreau C, Combarnous Y. Nitro-thiocyanobenzoic acid (NTCB) reactivity of cysteines beta100 and beta110 in porcine luteinizing hormone: metastability and hypothetical isomerization of the two disulfi de bridges of its beta-subunit seatbelt. Mol Cell Endocrinol 247, 175-182, 2006.10.1016/j.mce.2006.01.00116458419Search in Google Scholar

Brokken LJ, Bakker O, Wiersinga WM, Prummel MF. Functional thyrotropin receptor expression in the pituitary folliculo-stellate cell line TtT/GF. Exp Clin Endocrinol Diabetes 113, 13-20, 2005.10.1055/s-2004-83051615662590Search in Google Scholar

Cahoreau C, Klett D, Combarnous Y. Structure-function relationships of glycoprotein hormones and their subunits’ ancestors. Front Endocrinol (Lausanne) 6, 26, 2015.10.3389/fendo.2015.00026434156625767463Search in Google Scholar

Chan DW, Hui WW, Cai PC, Liu MX, Yung MM, Mak CS, Leung TH, Chan KK, Ngan HY. Targeting GRB7/ERK/ FOXM1 signaling pathway impairs aggressiveness of ovarian cancer cells. PLoS One 7, e52578, 2012.10.1371/journal.pone.0052578352759923285101Search in Google Scholar

Cheaib B, Auguste A, Leary A. Th e PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer 34, 4-16, 2015.10.5732/cjc.014.10289430208525556614Search in Google Scholar

Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 71, 717-721, 1983.Search in Google Scholar

Daly NL, Craik DJ. Bioactive cystine knot proteins. Curr Opin Chem Biol 15, 362-368, 2011.10.1016/j.cbpa.2011.02.00821362584Search in Google Scholar

Dos Santos S, Bardet C, Bertrand S, Escriva H, Habert D, Querat B. Distinct expression patterns of glycoprotein hormone-alpha2 and -beta5 in a basal chordate suggest independent developmental functions. Endocrinology 150, 3815-3822, 2009.10.1210/en.2008-174319264871Search in Google Scholar

Edmondson RJ, Monaghan JM, Davies BR. Gonadotropins mediate DNA synthesis and protection from spontaneous cell death in human ovarian surface epithelium. Int J Gynecol Cancer 16, 171-177, 2006.10.1111/j.1525-1438.2006.00274.x16445629Search in Google Scholar

Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531-1545, 1999.10.1093/genetics/151.4.1531146054810101175Search in Google Scholar

Fox KM, Dias JA, Van Roey P. Th ree-dimensional structure of human follicle-stimulating hormone. Mol Endocrinol 15, 378-389, 2001.10.1210/mend.15.3.060311222739Search in Google Scholar

Galet C, Lecompte F, Combarnous Y. Association/dissociation of gonadotropin subunits involves disulfi de bridge disruption which is infl uenced by carbohydrate moiety. Biochem Biophys Res Commun 324, 868-873, 2004.10.1016/j.bbrc.2004.09.14315474508Search in Google Scholar

Glaysher S, Bolton LM, Johnson P, Atkey N, Dyson M, Torrance C, Cree IA. Targeting EGFR and PI3K pathways in ovarian cancer. Br J Cancer 109, 1786-1794, 2013.10.1038/bjc.2013.529379018024022196Search in Google Scholar

Goto-Kazeto R, Kazeto Y, Trant JM. Molecular cloning, characterization and expression of thyroid-stimulating hormone receptor in channel catfi sh. Gen Comp Endocrinol 161, 313-319, 2009.10.1016/j.ygcen.2009.01.00919523396Search in Google Scholar

Gullberg H, Rudling M, Forrest D, Angelin B, Vennstrom B. Th yroid hormone receptor beta-defi cient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. Mol Endocrinol 14, 1739-1749, 2009.10.1210/mend.14.11.054811075809Search in Google Scholar

Hsu SY, Nakabayashi K, Bhalla A. Evolution of glycoprotein hormone subunit genes in bilateral metazoa: identifi cation of two novel human glycoprotein hormone subunit family genes, GPA2 and GPB5. Mol Endocrinol 16, 1538-1551, 2002.10.1210/mend.16.7.087112089349Search in Google Scholar

Huang WL, Li Z, Lin TY, Wang SW, Wu FJ, Luo CW. Th yrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway. Sci Rep 6, 27471, 2016.10.1038/srep27471489534127273257Search in Google Scholar

Ji TH, Ryu KS, Gilchrist R, Ji I. Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor. Recent Prog Horm Res 52, 431-453, 1997.Search in Google Scholar

Lantz M, Vondrichova T, Capretz A, Nilsson E, Frenander C, Bondeson AG, Ridderstrale M, Aberg M, Asman P, Groop L, Hallengren B. Thyrostimulin (a TSH-like Hormone) expression in orbital and thyroid tissue. Th yroid 17, 113-118, 2007.10.1089/thy.2006.015517316112Search in Google Scholar

Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, Morgan FJ, Isaacs NW. Crystal structure of human chorionic gonadotropin. Nature 369, 455-461, 1994.10.1038/369455a08202136Search in Google Scholar

Lash RW, Desai RK, Zimmerman CA, Flack MR, Yoshida T, Wondisford FE, Weintraub BD. Mutations of the human thyrotropin-beta subunit glycosylation site reduce thyrotropin synthesis independent of changes in glycosylation status. J Endocrinol Invest 15, 255-263, 1992.10.1007/BF033487231512415Search in Google Scholar

Macdonald LE, Wortley KE, Gowen LC, Anderson KD, Murray JD, Poueymirou WT, Simmons MV, Barber D, Valenzuela DM, Economides AN, Wiegand SJ, Yancopoulos GD, Sleeman MW, Murphy AJ. Resistance to dietinduced obesity in mice globally overexpressing OGH/GPB5. Proc Natl Acad Sci U S A 102, 2496-2501, 2005.10.1073/pnas.040984910254832715699348Search in Google Scholar

MacKenzie DS, Jones RA, Miller TC. Th yrotropin in teleost fi sh. Gen Comp Endocrinol 161, 83-89, 2009.10.1016/j.ygcen.2008.12.01019135445Search in Google Scholar

Matzuk MM, Boime I. Th e role of the asparagine-linked oligosaccharides of the alpha subunit in the secretion and assembly of human chorionic gonadotrophin. J Cell Biol 106, 1049-1059, 1988.10.1083/jcb.106.4.104921149942452167Search in Google Scholar

Nagasaki H, Wang Z, Jackson VR, Lin S, Nothacker HP, Civelli O. Diff erential expression of the thyrostimulin subunits, glycoprotein alpha2 and beta5 in the rat pituitary. J Mol Endocrinol 37, 39-50, 2006.10.1677/jme.1.0193216901922Search in Google Scholar

Nakabayashi K, Matsumi H, Bhalla A, Bae J, Mosselman S, Hsu SY, Hsueh AJ. Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest 109, 1445-1452, 2002.10.1172/JCI0214340Search in Google Scholar

Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE, Morgan M, Schlesselman JJ. Factors related to infl ammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 11, 111-117, 2000.10.1097/00001648-200003000-0000611021606Search in Google Scholar

Okada SL, Ellsworth JL, Durnam DM, Haugen HS, Holloway JL, Kelley ML, Lewis KE, Ren H, Sheppard PO, Storey HM, Waggie KS, Wolf AC, Yao LY, Webster PJ. A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor. Mol Endocrinol 20, 414-425, 2006.10.1210/me.2005-027016210345Search in Google Scholar

Okajima Y, Nagasaki H, Suzuki C, Suga H, Ozaki N, Arima H, Hamada Y, Civelli O, Oiso Y. Biochemical roles of the oligosaccharide chains in thyrostimulin, a heterodimeric hormone of glycoprotein hormone subunits alpha 2 (GPA2) and beta 5 (GPB5). Regul Pept 148, 62-67, 2008.10.1016/j.regpep.2008.03.00218433898Search in Google Scholar

Paluzzi JP, Vanderveken M, O’Donnell MJ. Th e heterodimeric glycoprotein hormone, GPA2/GPB5, regulates ion transport across the hindgut of the adult mosquito, Aedes aegypti. PLoS One 9, e86386, 2014.10.1371/journal.pone.0086386389647524466069Search in Google Scholar

Pierce JG, Parsons TF. Glycoprotein hormones: structure and function. Annu Rev Biochem 50, 465-495, 1981.10.1146/annurev.bi.50.070181.0023416267989Search in Google Scholar

Rae MT, Gubbay O, Kostogiannou A, Price D, Critchley HO, Hillier SG. Th yroid hormone signaling in human ovarian surface epithelial cells. J Clin Endocrinol Metab 92, 322-327, 2007.10.1210/jc.2006-152217032711Search in Google Scholar

Robinson SD, Li Q, Bandyopadhyay PK, Gajewiak J, Yandell M, Papenfuss AT, Purcell AW, Norton RS, Safavi-Hemami H. Hormone-like peptides in the venoms of marine cone snails. Gen Comp Endocrinol 244, 11-18, 2017.10.1016/j.ygcen.2015.07.012476275626301480Search in Google Scholar

Rocco DA, Paluzzi JP. Functional role of the heterodimeric glycoprotein hormone, GPA2/GPB5, and its receptor, LGR1: An invertebrate perspective. Gen Comp Endocrinol 234, 20-27, 2016.10.1016/j.ygcen.2015.12.01126704853Search in Google Scholar

Rocha A, Gomez A, Galay-Burgos M, Zanuy S, Sweeney GE, Carrillo M. Molecular characterization and seasonal changes in gonadal expression of a thyrotropin receptor in the European sea bass. Gen Comp Endocrinol 152, 89-101, 2007.10.1016/j.ygcen.2007.03.00117420017Search in Google Scholar

Ruddon RW, Sherman SA, Bedows E. Protein folding in the endoplasmic reticulum: lessons from the human chorionic gonadotropin beta subunit. Protein Sci 5, 1443-1452, 1996.10.1002/pro.556005080121434718844836Search in Google Scholar

Sellami A, Agricola HJ, Veenstra JA. Neuroendocrine cells in Drosophila melanogaster producing GPA2/GPB5, a hormone with homology to LH, FSH and TSH. Gen Comp Endocrinol 170, 582-588, 2011.10.1016/j.ygcen.2010.11.01521118692Search in Google Scholar

Shupnik MA, Ridgway EC, Chin WW. Molecular biology of thyrotropin. Endocr Rev 10, 459-475, 1989.10.1210/edrv-10-4-4592693083Search in Google Scholar

Sower SA, Decatur WA, Hausken KN, Marquis TJ, Barton SL, Gargan J, Freamat M, Wilmot M, Hollander L, Hall JA, Nozaki M, Shpilman M, Levavi-Sivan B. Emergence of an ancestral glycoprotein hormone in the pituitary of the sea lamprey, a basal vertebrate. Endocrinology 156, 3026-3037, 2015.10.1210/en.2014-179726066074Search in Google Scholar

Stockell Hartree A, Renwick AG. Molecular structures of glycoprotein hormones and functions of their carbohydrate components. Biochem J 287 (Pt 3), 665-679, 1992.10.1042/bj2870665Search in Google Scholar

Sudo S, Kuwabara Y, Park JI, Hsu SY, Hsueh AJ. Heterodimeric fl y glycoprotein hormone-alpha2 (GPA2) and glycoprotein hormone-beta5 (GPB5) activate fl y leucine-rich repeat-containing G protein-coupled receptor-1 (DLGR1) and stimulation of human thyrotropin receptors by chimeric fl y GPA2 and human GPB5. Endocrinology 146, 3596-3604, 2005.10.1210/en.2005-0317Search in Google Scholar

Sun SC, Hsu PJ, Wu FJ, Li SH, Lu CH, Luo CW. Th yrostimulin, but not thyroid-stimulating hormone (TSH), acts as a paracrine regulator to activate the TSH receptor in mammalian ovary. J Biol Chem 285, 3758-3765, 2010.10.1074/jbc.M109.066266Search in Google Scholar

Suzuki C, Nagasaki H, Okajima Y, Suga H, Ozaki N, Arima H, Iwasaki Y, Oiso Y. Infl ammatory cytokines regulate glycoprotein subunit beta5 of thyrostimulin through nuclear factor-kappaB. Endocrinology 150, 2237-2243, 2009.10.1210/en.2008-0823Search in Google Scholar

Tando Y, Kubokawa K. Expression of the gene for ancestral glycoprotein hormone beta subunit in the nerve cord of amphioxus. Gen Comp Endocrinol 162, 329-339, 2009a.10.1016/j.ygcen.2009.04.015Search in Google Scholar

Tando Y, Kubokawa K. A homolog of the vertebrate thyrostimulin glycoprotein hormone alpha subunit (GPA2) is expressed in Amphioxus neurons. Zoolog Sci 26, 409-414, 2009b.10.2108/zsj.26.409Search in Google Scholar

te Velde ER, Scheff er GJ, Dorland M, Broekmans FJ, Fauser BC. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 145, 67-73, 1998.10.1016/S0303-7207(98)00171-3Search in Google Scholar

Thotakura NR, Blithe DL. Glycoprotein hormones: glycobiology of gonadotrophins, thyrotrophin and free alpha subunit. Glycobiology 5, 3-10, 1995.10.1093/glycob/5.1.3Search in Google Scholar

Tonary AM, Macdonald EA, Faught W, Senterman MK, Vanderhyden BC. Lack of expression of c-KIT in ovarian cancers is associated with poor prognosis. Int J Cancer 89, 242-250, 2000.10.1002/1097-0215(20000520)89:3<242::AID-IJC6>3.0.CO;2-6Search in Google Scholar

Tsutsui S, Yasuda K, Suzuki K, Takeuchi H, Nishizaki T, Higashi H, Era S. A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer. Br J Cancer 94, 1874-1878, 2006.10.1038/sj.bjc.6603183Search in Google Scholar

van Zeijl CJ, Surovtseva OV, Wiersinga WM, Boelen A, Fliers E. Transient hypothyroxinemia in juvenile glycoprotein hormone subunit B5 knock-out mice. Mol Cell Endocrinol 321, 231-238, 2010.10.1016/j.mce.2010.03.00220223276Search in Google Scholar

van Zeijl CJ, Surovtseva OV, Wiersinga WM, Fliers E, Boelen A. Acute infl ammation increases pituitary and hypothalamic glycoprotein hormone subunit B5 mRNA expression in association with decreased thyrotrophin receptor mRNA expression in mice. J Neuroendocrinol 23, 310-319, 2011.10.1111/j.1365-2826.2011.02116.x21314737Search in Google Scholar

van Zeijl CJ, Surovtseva OV, Kwakkel J, van Beeren HC, Bassett JH, Williams GR, Wiersinga WM, Fliers E, Boelen A. Thyrostimulin defi ciency does not alter peripheral responses to acute infl ammation-induced nonthyroidal illness. Am J Physiol Endocrinol Metab 307, E527-E537, 2014.10.1152/ajpendo.00266.201425117405Search in Google Scholar

Yoshimura M, Hershman JM. Th yrotropic action of human chorionic gonadotropin. Th yroid 5, 425-434, 1995.10.1089/thy.1995.5.4258563483Search in Google Scholar

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