Thyroid-stimulating hormone (TSH) has long served as the primary biomarker guiding the diagnosis and management of hypothyroidism. Following the introduction of sensitive TSH assays in the 1970s and the recognition of peripheral conversion of thyroxine (T4) to triiodothyronine (T3), normalization of serum TSH became the central therapeutic target in thyroid hormone replacement therapy. This paradigm has improved treatment safety and standardization; however, a persistent clinical paradox has emerged: a subset of patients treated with levothyroxine achieve biochemical euthyroidism based on TSH criteria yet continue to experience symptoms suggestive of impaired thyroid hormone action.

In response, divergent clinical perspectives have developed. Conventional endocrine practice continues to prioritize TSH normalization as the principal indicator of adequate therapy, whereas some emerging approaches de-emphasize TSH in favor of symptom-based management. Both perspectives risk oversimplifying the complex, multi-level regulation of thyroid hormone physiology. While TSH reflects hypothalamic–pituitary–thyroid (HPT) axis feedback, it does not fully capture tissue-level thyroid hormone signaling, which is influenced by factors including hormone transport, deiodinase activity, receptor isoform distribution, inflammatory signaling, and metabolic context.

This review examines the physiologic role of TSH, the historical evolution of TSH-centric thyroid management, and the limitations of relying on TSH as a sole marker of thyroid hormone sufficiency. At the same time, it underscores the continued importance of TSH as a systemic safety signal, given well-established associations between suppressed TSH and adverse cardiovascular and skeletal outcomes. We propose a systems-based framework for interpreting thyroid function that integrates TSH with circulating thyroid hormone levels, metabolic and inflammatory markers, and clinical phenotype. This approach aims to reconcile current debates in thyroid medicine and support a more precise, physiology-informed model of thyroid hormone replacement.