Personalized Approaches to Hypothyroidism: The Role of Triiodothyronine (T3) in Thyroid Hormone Replacement

Levothyroxine (T4) monotherapy remains the standard of care for hypothyroidism worldwide. However, a subset of patients continues to report persistent symptoms, such as fatigue, depression, and cognitive difficulties, despite normalized thyroid-stimulating hormone (TSH) levels. This has reignited clinical interest in the active thyroid hormone triiodothyronine (T3) and combination T4/T3 therapies. This review explores the physiological distinctions between T4 and T3, emphasizing the importance of peripheral T4-to-T3 conversion and the role of deiodinase polymorphisms (e.g., DIO2 Thr92Ala) that may impair this process in certain individuals. The evidence for T3-containing therapies is critically evaluated, including synthetic liothyronine and desiccated thyroid extract, comparing their pharmacokinetics, clinical outcomes, and safety profiles with T4 monotherapy. Emerging data suggest that some patients may benefit from combination therapy, particularly in symptom resolution and quality-of-life measures, although robust long-term outcomes remain under debate. Current clinical guidelines from major thyroid societies continue to endorse T4 monotherapy, citing inconsistent trial results and potential cardiovascular risks associated with T3. Nonetheless, a growing movement toward personalized medicine, including genetic profiling, patient-reported outcomes, and individualized dosing, may pave the way for more nuanced treatment strategies. This review underscores the need for a balanced, patient-centered approach to thyroid hormone replacement, integrating evolving science with clinical experience to optimize care for individuals with hypothyroidism.