{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:46:03Z","timestamp":1785732363366,"version":"3.56.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>A common concern during thyroid hormone replacement therapy is over-substitution leading to increased risk of primarily osteoporotic fracture, and adverse cardiac outcomes in particular. The addition of synthetic triiodothyronine (T3) to treatment regimens for hypothyroidism has been singled out as being associated with a higher risk of such adverse effects. While thyroid-stimulating hormone (TSH) has been a universally accepted, useful parameter for monitoring treatment responses in thyroid diseases, it is not perfect. This is highlighted by the fact, that 5-10% of patients with hypothyroidism continue to exhibit hypothyroid symptoms, despite normal circulating TSH levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>While assessment of intracellular T3 concentrations is impossible, biomarkers reflecting the cellular action of intracellular T3 binding to nuclear receptors may be informative than assessing extracellular thyroid hormone concentrations. The aim of this study was therefore twofold: 1) to investigate the variation between TSH levels and four biomarkers related to thyroid hormone action (N-terminal pro b-type natriuretic peptide (NT-proBNP), N-terminal propeptide of type I collagen (PINP), sex hormone binding globulin (SHBG) and low-density lipoprotein cholesterol (LDL-C) with different TSH levels and 2) to assess whether these biomarkers differed among patients receiving three different treatment regimens: synthetic thyroxine (T4) monotherapy, T3 monotherapy and T4\/T3 combination therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SHBG revealed a steady significant increase within the reference range with decreasing TSH (p&amp;lt;0.001), with the highest values being reached at TSH &amp;lt; 0.01 mIU\/L. LDL-C, however, did not show significant variation with TSH. NT-proBNP also revealed a significant increase within the reference range with decreasing TSH (p= 0.002), while PINP exhibited an inverse relationship (p=0.042). When analyzing biomarkers in relation to treatment regimen, the following patterns emerged: In patients on T3 monotherapy, SHBG was significantly higher (p&amp;lt;0.001), and LDL-C significantly lower (p=0.045) compared to the other groups. NT-proBNP and PINP, however, did not show any significant differences between the three treatment groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our results suggest that in a subgroup of hypothyroid patients, with persistent hypothyroid symptoms, T3 monotherapy may further enhance the clinical effects of thyroid hormone substitution therapy, without increasing the risk of adverse effects at the heart and skeleton.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1919606","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:26:07Z","timestamp":1785731167000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of biomarkers of thyroid hormone action across three thyroid hormone replacement regimens in 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