{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:32:24Z","timestamp":1753878744095,"version":"3.41.2"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Defined by thyroid\u2010pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials &amp; methods<\/jats:title><jats:p>A system of five coupled first\u2010order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4\u2010T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4\u2010T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback\u2010feedforward control of the hypothalamic\u2010pituitary\u2010thyroid regulation. Strong T3\u2010protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide\u2010ranging implications for the utility of TSH in clinical decision\u2010making.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.13192","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T10:07:15Z","timestamp":1575886035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1326-4270","authenticated-orcid":false,"given":"Rudolf","family":"Hoermann","sequence":"first","affiliation":[{"name":"Department for Nuclear Medicine Klinikum L\u00fcdenscheid L\u00fcdenscheid Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-5889","authenticated-orcid":false,"given":"Mark J.","family":"Pekker","sequence":"additional","affiliation":[{"name":"Mathematical Sciences Department University of Alabama Huntsville AL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John E. M.","family":"Midgley","sequence":"additional","affiliation":[{"name":"North Lakes Clinical Ilkley UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf","family":"Larisch","sequence":"additional","affiliation":[{"name":"Department for Nuclear Medicine Klinikum L\u00fcdenscheid L\u00fcdenscheid Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-3549","authenticated-orcid":false,"given":"Johannes W.","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Medical Department I, Endocrinology and Diabetology Bergmannsheil University Hospitals Ruhr University of Bochum Bochum Germany"},{"name":"Ruhr Center for Rare Diseases (CeSER) Ruhr University of Bochum and Witten\/Herdecke University Bochum Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-27-2-251"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0028"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(18)30371-1"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l2006"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00275"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00177"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00091"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12527"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3413\/Nukmed-0671-14-06"},{"key":"e_1_2_8_11_1","first-page":"333","article-title":"Die Kinetik der Invertinwirkung","volume":"49","author":"Michaelis L","year":"1913","journal-title":"Biochem Zeitschr"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-57-3-500"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-112-2-417"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0140171"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0184-8"},{"key":"e_1_2_8_16_1","unstructured":"DietrichJW.Simthyr 4.0.1. 2019. RRID: Scr_014351.https:\/\/simthyr.sourceforge.io. Accessed May 15 2019."},{"key":"e_1_2_8_17_1","first-page":"329","article-title":"Fractal properties of the thyrotropic feedback control implications of a nonlinear model compared with empirical data","volume":"35","author":"Dietrich JW","year":"2002","journal-title":"Proc Cybernetics Syst"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/01969720490443354"},{"key":"e_1_2_8_19_1","first-page":"269","article-title":"Equilibrium behaviour of feedback\u2010coupled physiological saturation kinetics","volume":"1","author":"Dietrich JW","year":"2006","journal-title":"Cybernetics Syst"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/351864"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2016.00057"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0819"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2012-201213"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0187232"},{"volume-title":"R: A Language and Environment for Statistical Computing","year":"2019","author":"R Core Team","key":"e_1_2_8_25_1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4020-8624-3_1"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cam.2013.10.034"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1995.tb01894.x"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1398616"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0189-2"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00163"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0095"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.66"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00286"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77588"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.155"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198201073060107"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1184"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00664"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.3.8165"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00364"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1159\/000447967"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-1029"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2016.0426"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Feci.13192","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.13192","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/eci.13192","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.13192","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T13:27:15Z","timestamp":1694093235000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.13192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,28]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1111\/eci.13192"],"URL":"https:\/\/doi.org\/10.1111\/eci.13192","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"type":"print","value":"0014-2972"},{"type":"electronic","value":"1365-2362"}],"subject":[],"published":{"date-parts":[[2020,1,28]]},"assertion":[{"value":"2019-06-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13192"}}