{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T17:36:57Z","timestamp":1767202617512,"version":"build-2238731810"},"reference-count":317,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The 2012 American endocrine associations' guidelines on hypothyroidism were a reiteration of the TSH-T4 Paradigm from the 1970s. They likewise defined hypothyroidism as hypothyroxinemia, assumed that almost all hypothyroidism was primary, and relied upon the thyroid stimulating hormone (TSH) test and inactive prohormone thyroxine (T4) for diagnosis and treatment. The guidelines\u2019 authors acknowledged many TSH and other \u201cpitfalls\u201d in the paradigm yet warned physicians against attending to patients\u2019 signs and symptoms and relative free T4 (FT4) and free triiodothyronine (FT3) levels\u2014the only means by which to identify and avoid all pitfalls and provide individualized diagnosis and treatment. This inadequate paradigm has distorted medical practice and research for 50 years, including laboratories\u2019 FT4 and FT3 reference ranges. It produces overdiagnosis, underdiagnosis, inadequate treatment, and widespread patient dissatisfaction. Since the 1970s, our understanding of thyroid hormone production, transport, metabolism, reception, and signaling has increased greatly, as has our appreciation of the importance of optimal T3 effects for health and wellbeing. Hypothyroidism must be defined physiologically as insufficient T3 effect in some or all tissues. The best indicators of tissue T3 effect are the patient\u2019s signs and symptoms, and the best serum tests are FT4 and FT3, considered together. The TSH level is not a reliable indicator of T3 status in the untreated state and is oversuppressed by the peak levels that occur with once-daily oral T4 and\/or T3. Normalizing an elevated TSH or low FT4 with T4 usually does not produce sufficient, let alone optimal, T3 effect and can leave some patients markedly hypothyroid. T4\/T3 combination therapy is more physiological and effective than T4 monotherapy and must be guided by clinical criteria, not the TSH. Some patients cannot tolerate more T3 effect due to hypocortisolism, inflammation, and other disorders. There is no substitute for the practice of fully informed clinical medicine.<\/jats:p>","DOI":"10.3389\/fendo.2025.1529791","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:10:34Z","timestamp":1750723834000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical thyroidology: beyond the 1970s\u2019 TSH-T4 Paradigm"],"prefix":"10.3389","volume":"16","author":[{"given":"Henry H.","family":"Lindner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"B1","first-page":"211","volume-title":"Basic and Clinical Endocrinology","author":"Greenspan","year":"1991"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1113\/eph8802506","article-title":"Regulation of mitochondrial biogenesis by thyroid hormone","volume":"88","author":"Weitzel","year":"2003","journal-title":"Exp Physiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms160716158","article-title":"Thyroid hormone mediated modulation of energy expenditure","volume":"16","author":"Vaitkus","year":"2015","journal-title":"Int J Mol Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-56-3-479","article-title":"The effect of thyroid hormones on gluconeogenesis and forearm metabolism in man","volume":"56","author":"Sandler","year":"1983","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s1043-2760(00)00263-0","article-title":"Gene regulation by thyroid hormone","volume":"11","author":"Wu","year":"2000","journal-title":"Trends Endocrinol Metab"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2014.05.023","article-title":"A temporary compendium of thyroid hormone target genes in brain","volume":"1849","author":"Chatonnet","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1210\/edrv.23.1.0455","article-title":"Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases","volume":"23","author":"Bianco","year":"2002","journal-title":"Endocr Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1210\/edrv.23.1.0455","article-title":"Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling","volume":"29","author":"Gereben","year":"2008","journal-title":"Endocr Rev"},{"key":"B9","article-title":"Metabolism of thyroid hormone","volume-title":"Endotext","author":"Peeters","year":"2000"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/endo.137.6.8641203","article-title":"Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat","volume":"137","author":"Escobar-Morreale","year":"1996","journal-title":"Endocrinology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/me.2006-0035","article-title":"Thyroid hormones signaling is getting more complex: STORMs are coming","volume":"21","author":"Flamant","year":"2007","journal-title":"Mol Endocrinol"},{"key":"B12","article-title":"Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action","volume-title":"Endotext [Internet]","author":"Dumitrescu","year":"2023"},{"key":"B13","doi-asserted-by":"publisher","first-page":"988","DOI":"10.4158\/ep12280.gl","article-title":"American association of clinical endocrinologists and american thyroid association taskforce on hypothyroidism in adults 2012 clinical practice guidelines for hypothyroidism in adults: co-sponsored by american association of clinical endocrinologists and the American thyroid association","volume":"18","author":"Garber","year":"2012","journal-title":"Endocr Pract"},{"key":"B14","volume-title":"The Structure of Scientific Revolutions","author":"Kuhn","year":"1962"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-67-1-90","article-title":"A new synthetic thyroid hormone combination for clinical therapy","volume":"67","author":"Selenkow","year":"1967","journal-title":"Ann Intern Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2020.0153","article-title":"Liothyronine and desiccated thyroid extract in the treatment of hypothyroidism","volume":"10","author":"Idrees","year":"2020","journal-title":"Thyroid"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(56)90159-0","article-title":"Therapeutic activity of desiccated thyroid substance, sodium L-thyroxine and D, L-triiodothyronine; 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