Beyond TSH: Persistent Symptoms in LT4-Treated Hypothyroidism

Hypothyroidism is one of the most common endocrine disorders worldwide, and levothyroxine (LT4) monotherapy remains the standard of care. Although most patients achieve biochemical euthyroidism based on serum thyroid-stimulating hormone (TSH) levels, a substantial proportion—estimated at 10–20%—continue to report persistent symptoms, including fatigue, weight gain, cognitive impairment, and reduced quality of life. This discrepancy between normalized TSH levels and ongoing clinical complaints represents a significant and unresolved challenge in contemporary endocrinology.The current paradigm assumes that normalization of serum TSH reflects adequate thyroid hormone action at the tissue level. However, emerging evidence suggests that this assumption may be overly simplistic. Variability in peripheral thyroid hormone metabolism, including differences in deiodinase activity, intracellular T3 availability, and tissue-specific regulation, may contribute to persistent symptoms in some patients. Additionally, factors such as genetic polymorphisms, chronic inflammation, gut microbiota composition, and comorbid conditions may further modulate the clinical response to LT4 therapy.Recent years have seen renewed interest in alternative therapeutic strategies, particularly combination therapy with LT4 and liothyronine (LT3). While randomized trials have yielded mixed results, some patients report subjective improvement, highlighting the need for better patient selection and more precise biomarkers of thyroid hormone action. At the same time, large observational studies have begun to explore long-term outcomes associated with different therapeutic approaches, including cardiovascular risk, metabolic parameters, and neurocognitive endpoints.This Research Topic aims to provide a comprehensive and multidisciplinary overview of persistent symptoms in LT4-treated hypothyroidism, moving beyond a TSH-centered model toward a more individualized understanding of thyroid hormone physiology and therapy. We particularly encourage submissions spanning clinical, translational, and basic science research, fostering integration between mechanistic insights and patient-centered outcomes.We welcome original research articles, systematic reviews, meta-analyses, and expert perspectives addressing (but not limited to):(1) molecular mechanisms underlying persistent symptoms;(2) the role of T3 and tissue-level thyroid hormone action;(3) clinical trials and real-world data on combination therapy;(4) novel biomarkers beyond TSH;(5) biological rhythms of the hypothalamic–pituitary–thyroid axis and potential targets for chronotherapy;(6) the impact of gut microbiota and inflammation; and(7) patient-reported outcomes and quality of life.By integrating clinical, translational, and mechanistic perspectives, this Topic seeks to advance the field toward more personalized and effective management strategies for patients with hypothyroidism. Topic editors: Gustavo Penna, Paula Bargi-Souza, Danilo Villagelin, Magda Pires, Laura Sterian Ward, Federico Salas-Lucia Source: https://www.frontiersin.org/research-topics/81495/beyond-tsh-persistent-symptoms-in-lt4-treated-hypothyroidism