{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:10:33Z","timestamp":1790201433449,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyrostimulin is a heterodimeric glycoprotein hormone composed of two subunits, GPA2 and GPB5, first identified in 2002. It is considered an ancestral member of the glycoprotein hormone family and is highly conserved across species, including vertebrates and invertebrates. Unlike classical pituitary glycoprotein hormones such as TSH, LH, and FSH, thyrostimulin appears to function predominantly through paracrine and autocrine mechanisms, with its expression reported in diverse tissues such as the pituitary, ovary, skin, and brain. In humans, thyrostimulin has been implicated in ovarian cancer cell proliferation, stem cell quiescence in the pituitary, and metabolic regulation. However, its role in metabolism remains unclear, with studies showing both beneficial and adverse effects such as weight loss in some models and elevated levels in polycystic ovary syndrome and metabolic syndrome patients. In Caenorhabditis elegans, orthologs of GPA2 and GPB5 have been shown to influence growth and intestinal function via a neuroendocrine pathway involving thyrotropin hormone-like peptides. These findings suggest that thyrostimulin has conserved multifunctional roles in development, metabolism, and endocrine signaling. The aim of this review is to summarize the structure\u2013function relationships and the currently known roles of thyrostimulin and its subunits, GPA2\/GPB5, particularly in the reproductive system, metabolic syndrome, skeletal development, and obesity.<\/jats:p>","DOI":"10.3390\/ijms262311523","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:31:52Z","timestamp":1764261112000},"page":"11523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular and Functional Insights into Thyrostimulin and Its Subunits-GPA2\/GPB5"],"prefix":"10.3390","volume":"26","author":[{"given":"Nasreen","family":"Nakad","sequence":"first","affiliation":[{"name":"Department of Human Biology, University of Haifa, Mount Carmel, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-8847","authenticated-orcid":false,"given":"Fuad","family":"Fares","sequence":"additional","affiliation":[{"name":"Department of Human Biology, University of Haifa, Mount Carmel, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1172\/JCI0214340","article-title":"Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor","volume":"109","author":"Nakabayashi","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1210\/mend.16.7.0871","article-title":"Evolution of glycoprotein hormone subunit genes in bilateral metazoa: Identification of two novel human glycoprotein hormone subunit family genes, GPA2 and GPB5","volume":"16","author":"Hsu","year":"2002","journal-title":"Mol. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Querat, B. (2021). Unconventional Actions of Glycoprotein Hormone Subunits: A Comprehensive Review. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.731966"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1146\/annurev.bi.50.070181.002341","article-title":"Glycoprotein hormones: Structure and function","volume":"50","author":"Pierce","year":"1981","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Alvarez, E., Cahoreau, C., and Combarnous, Y. (2009). 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.","DOI":"10.1186\/1477-7827-7-90"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1210\/me.2005-0270","article-title":"A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor","volume":"20","author":"Okada","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.mce.2010.03.002","article-title":"Transient hypothyroxinemia in juvenile glycoprotein hormone subunit B5 knock-out mice","volume":"321","author":"Surovtseva","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1074\/jbc.M109.066266","article-title":"Thyrostimulin, but not thyroid-stimulating hormone (TSH), acts as a paracrine regulator to activate the TSH receptor in mammalian ovary","volume":"285","author":"Sun","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Huang, W.L., Li, Z., Lin, T.-Y., Wang, S.-W., Wu, F.-J., and Luo, C.-W. (2016). Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway. Sci. Rep., 6.","DOI":"10.1038\/srep27471"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1210\/en.2009-0306","article-title":"Thyroid-stimulating hormone, a novel, locally produced modulator of human epidermal functions, is regulated by thyrotropin-releasing hormone and thyroid hormones","volume":"151","author":"Bodo","year":"2010","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hausken, K., and Levavi-Sivan, B. (2019). Synteny and phylogenetic analysis of paralogous thyrostimulin beta subunits (GpB5) in vertebrates. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222808"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13733","DOI":"10.1016\/S0021-9258(17)36705-4","article-title":"The human thyrotropin receptor activates G-proteins Gs and Gq\/11","volume":"269","author":"Allgeier","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1146\/annurev.bb.24.060195.001413","article-title":"The cystine-knot growth-factor superfamily","volume":"24","author":"Sun","year":"1995","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.regpep.2008.03.002","article-title":"Biochemical roles of the oligosaccharide chains in thyrostimulin, a heterodimeric hormone of glycoprotein hormone subunits alpha 2 (GPA2) and beta 5 (GPB5)","volume":"148","author":"Okajima","year":"2008","journal-title":"Regul. Pept."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1515\/enr-2017-0012","article-title":"The role of thyrostimulin and its potential clinical significance","volume":"51","author":"Karponis","year":"2017","journal-title":"Endocr. Regul."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cahoreau, C., Klett, D., and Combarnous, Y. (2015). Structure-function relationships of glycoprotein hormones and their subunits\u2019 ancestors. Front. Endocrinol., 6.","DOI":"10.3389\/fendo.2015.00026"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1016\/S0021-9258(20)89587-8","article-title":"Delineation via site-directed mutagenesis of the carboxyl-terminal region of human choriogonadotropin beta required for subunit assembly and biological activity","volume":"266","author":"Chen","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.bbagen.2005.12.022","article-title":"The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: Development of agonists and antagonists","volume":"1760","author":"Fares","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1016\/S0021-9258(19)81628-9","article-title":"Site Specificity of the Chorionic-Gonadotropin N-Linked Oligosaccharides in Signal Transduction","volume":"264","author":"Matzuk","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1095\/biolreprod40.1.48","article-title":"Mutagenesis and Gene-Transfer Define Site-Specific Roles of the Gonadotropin Oligosaccharides","volume":"40","author":"Matzuk","year":"1989","journal-title":"Biol. Reprod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1074\/jbc.M008093200","article-title":"Engineering a potential antagonist of human thyrotropin and thyroid-stimulating antibody","volume":"276","author":"Fares","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1210\/en.2005-0012","article-title":"Human thyrotropin (TSH) variants designed by site-directed mutagenesis block TSH activity in vitro and in vivo","volume":"146","author":"Azzam","year":"2005","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Azzam, N., Bar-Shalom, R., and Fares, F. (2021). A Novel Follitropin Analog Inhibits Follitropin Activity In Vitro. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030325"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/BF03348723","article-title":"Mutations of the human thyrotropin-\u03b2 subunit glycosylation site reduce thyrotropin synthesis independent of changes in glycosylation status","volume":"15","author":"Lash","year":"1992","journal-title":"J. Endocrinol. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"112553","DOI":"10.1016\/j.mce.2025.112553","article-title":"Pleiotropic signaling of single-chain thyrostimulin (GPB5-GPA2) on homologous glycoprotein hormone receptors (ScFSHR, ScLHR, ScTSHR) in the elasmobranch reproduction","volume":"604","author":"Jeanne","year":"2025","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1172\/JCI0216234","article-title":"The TSH receptor reveals itself","volume":"110","author":"Davies","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4048","DOI":"10.1210\/en.2004-0437","article-title":"Minireview: Structural and functional evolution of the thyrotropin receptor","volume":"145","author":"Farid","year":"2004","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/gene.2008.69","article-title":"Bone marrow cells produce a novel TSH\u03b2 splice variant that is upregulated in the thyroid following systemic virus infection","volume":"10","author":"Vincent","year":"2009","journal-title":"Genes Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1210\/en.2015-1974","article-title":"T3 Regulates a Human Macrophage-Derived TSH-\u03b2 Splice Variant: Implications for Human Bone Biology","volume":"157","author":"Baliram","year":"2016","journal-title":"Endocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.mce.2013.08.021","article-title":"Structural biology of glycoprotein hormones and their receptors: Insights to signaling","volume":"382","author":"Jiang","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1210\/en.2008-0878","article-title":"Characterization of Thyrotropin Receptor Antibody-Induced Signaling Cascades","volume":"150","author":"Morshed","year":"2009","journal-title":"Endocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Latif, R., Morshed, S.A., Ma, R., Tokat, B., Mezei, M., and Davies, T.F. (2020). A Gq Biased Small Molecule Active at the TSH Receptor. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00372"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1210\/en.2014-1943","article-title":"Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development","volume":"156","author":"Bassett","year":"2015","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112163","DOI":"10.1016\/j.mce.2024.112163","article-title":"Glycoprotein hormone subunit alpha 2 (GPHA2): A pituitary stem cell-expressed gene associated with NOTCH2 signaling","volume":"586","author":"Ge","year":"2024","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1073\/pnas.0409849102","article-title":"Resistance to diet-induced obesity in mice globally overexpressing OGH\/GPB5","volume":"102","author":"Macdonald","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1530\/JOE-11-0404","article-title":"TSH-induced gene expression involves regulation of self-renewal and differentiation-related genes in human bone marrow-derived mesenchymal stem cells","volume":"212","author":"Bagriacik","year":"2012","journal-title":"J. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1210\/en.2005-0317","article-title":"Heterodimeric fly glycoprotein hormone-\u03b12 (GPA2) and glycoprotein hormone-\u03b25 (GPB5) activate fly leucine-rich repeat-containing G protein-coupled receptor-1 (DLGR1) and stimulation of human thyrotropin receptors by chimeric fly GPA2 and human GPB5","volume":"146","author":"Sudo","year":"2005","journal-title":"Endocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"170710","DOI":"10.1016\/j.peptides.2021.170710","article-title":"Exploring the role of glycoprotein hormone GPA2\/GPB5 in the medically important insect, Rhodnius prolixus","volume":"149","author":"Kuwabara","year":"2022","journal-title":"Peptides"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Paluzzi, J.P., Vanderveken, M., and O\u2019Donnell, M.J. (2014). The heterodimeric glycoprotein hormone, GPA2\/GPB5, regulates ion transport across the hindgut of the adult mosquito, Aedes aegypti. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086386"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.ygcen.2010.11.015","article-title":"Neuroendocrine cells in Drosophila melanogaster producing GPA2\/GPB5, a hormone with homology to LH, FSH and TSH","volume":"170","author":"Sellami","year":"2011","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kenis, S., Istiban, M.N., Van Damme, S., Vandewyer, E., Watteyne, J., Schoofs, L., and Beets, I. (2023). Ancestral glycoprotein hormone-receptor pathway controls growth in C. elegans. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1200407"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1111\/j.1365-2443.2009.01341.x","article-title":"FLR-2, the glycoprotein hormone alpha subunit, is involved in the neural control of intestinal functions in Caenorhabditis elegans","volume":"14","author":"Oishi","year":"2009","journal-title":"Genes Cells"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1073\/pnas.1910262116","article-title":"Corazonin signaling integrates energy homeostasis and lunar phase to regulate aspects of growth and sexual maturation in Platynereis","volume":"117","author":"Andreatta","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5440","DOI":"10.1210\/en.2012-1677","article-title":"Distinct expression patterns of glycoprotein hormone subunits in the lophotrochozoan Aplysia: Implications for the evolution of neuroendocrine systems in animals","volume":"153","author":"Heyland","year":"2012","journal-title":"Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ygcen.2015.07.012","article-title":"Hormone-like peptides in the venoms of marine cone snails","volume":"244","author":"Robinson","year":"2017","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ygcen.2010.02.010","article-title":"Neurohormones and neuropeptides encoded by the genome of Lottia gigantea, with reference to other mollusks and insects","volume":"167","author":"Veenstra","year":"2010","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1126\/science.1080049","article-title":"The draft genome of Ciona intestinalis: Insights into chordate and vertebrate origins","volume":"298","author":"Dehal","year":"2002","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2108\/zsj.26.409","article-title":"A homolog of the vertebrate thyrostimulin glycoprotein hormone alpha subunit (GPA2) is expressed in Amphioxus neurons","volume":"26","author":"Tando","year":"2009","journal-title":"Zool. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1210\/en.2008-1743","article-title":"Distinct Expression Patterns of Glycoprotein Hormone-\u03b12 and -\u03b25 in a Basal Chordate Suggest Independent Developmental Functions","volume":"150","author":"Bardet","year":"2009","journal-title":"Endocrinology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ygcen.2015.12.011","article-title":"Functional role of the heterodimeric glycoprotein hormone, GPA2\/GPB5, and its receptor, LGR1: An invertebrate perspective","volume":"234","author":"Rocco","year":"2016","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1385\/ENDO:26:3:267","article-title":"Conservation of the heterodimeric glycoprotein hormone subunit family proteins and the LGR signaling system from nematodes to humans","volume":"26","author":"Park","year":"2005","journal-title":"Endocrine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1677\/jme.1.01932","article-title":"Differential expression of the thyrostimulin subunits, glycoprotein \u03b12 and \u03b25 in the rat pituitary","volume":"37","author":"Nagasaki","year":"2006","journal-title":"J. Mol. Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1210\/edrv-10-4-459","article-title":"Molecular biology of thyrotropin","volume":"10","author":"Shupnik","year":"1989","journal-title":"Endocr. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1089\/thy.2000.10.387","article-title":"Congenital central isolated hypothyroidism caused by a homozygous mutation in the TSH-\u03b2 subunit gene","volume":"10","author":"Heinrichs","year":"2000","journal-title":"Thyroid"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.stemcr.2015.11.001","article-title":"Notch-Dependent Pituitary SOX2(+) Stem Cells Exhibit a Timed Functional Extinction in Regulation of the Postnatal Gland","volume":"5","author":"Zhu","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.stem.2021.04.003","article-title":"Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing","volume":"28","author":"Altshuler","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jtos.2021.03.010","article-title":"A single cell atlas of human cornea that defines its development, limbal progenitor cells and their interactions with the immune cells","volume":"21","author":"Collin","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S1472-6483(10)60091-0","article-title":"Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue","volume":"18","author":"Aghajanova","year":"2009","journal-title":"Reprod. Biomed. Online"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1093\/emboj\/19.12.2900","article-title":"Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes","volume":"19","author":"Busca","year":"2000","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.mehy.2014.05.009","article-title":"A role for cAMP-driven transactivation of EGFR in cancer aggressiveness\u2014Therapeutic implications","volume":"83","author":"McCarty","year":"2014","journal-title":"Med. Hypotheses"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1038\/sj.onc.1210422","article-title":"Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer","volume":"26","author":"Roberts","year":"2007","journal-title":"Oncogene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9572","DOI":"10.1074\/jbc.275.13.9572","article-title":"The \u03b22-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor","volume":"275","author":"Maudsley","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1677\/ERC-09-0152","article-title":"Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1\/2 activation regulated by calcium and protein kinase C\u03b4","volume":"17","author":"Bolitho","year":"2010","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ygcen.2009.01.009","article-title":"Molecular cloning, characterization and expression of thyroid-stimulating hormone receptor in channel catfish","volume":"161","author":"Kazeto","year":"2009","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xiang, T., Xia, X., Zhang, H., Geng, S., Yang, G., Qiu, S., He, Y., Liu, R., and Li, L. (2022). Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1010714"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/humrep\/dep399","article-title":"The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria","volume":"25","author":"March","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications","volume":"33","author":"Dunaif","year":"2012","journal-title":"Endocr. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"E2539","DOI":"10.1210\/jc.2014-1180","article-title":"Circulating irisin and glucose-dependent insulinotropic peptide are associated with the development of polycystic ovary syndrome","volume":"99","author":"Chang","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1046\/j.1365-2265.2000.01000.x","article-title":"Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: A retrospective cohort study","volume":"52","author":"Wild","year":"2000","journal-title":"Clin. Endocrinol."},{"key":"ref_70","first-page":"774","article-title":"Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis","volume":"18","author":"Dunaif","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"264","DOI":"10.3109\/09513590.2014.984676","article-title":"Adiponectin and leptin in overweight\/obese and lean women with polycystic ovary syndrome","volume":"31","author":"Chen","year":"2015","journal-title":"Gynecol. Endocrinol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/sj.ijo.0801994","article-title":"Obesity and the polycystic ovary syndrome","volume":"26","author":"Gambineri","year":"2002","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Xiang, T., Zhang, S., Li, Q., Li, L., Liu, H., Chen, C., Yang, G., and Yang, M. (2022). GPHB5 Is a Biomarker in Women With Metabolic Syndrome: Results From Cross-Sectional and Intervention Studies. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.893142"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1006\/dbio.2001.0487","article-title":"Tissue origins and interactions in the mammalian skull vault","volume":"241","author":"Jiang","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_75","first-page":"1739","article-title":"Thyroid hormone receptor \u03b2-deficient mice show complete loss of the normal cholesterol 7\u03b1-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol","volume":"14","author":"Gullberg","year":"2000","journal-title":"Mol. Endocrinol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T05:29:12Z","timestamp":1764394152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":75,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311523"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311523","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}