The History and Future of Treatment of Hypothyroidism

Abstract

Thyroid hormone replacement has been used for more than a century to treat hypothyroidism. Natural thyroid preparations (thyroid extract, desiccated thyroid, or thyroglobulin), which contain both thyroxine (T4) and triiodothyronine (T3), were the first pharmacologic treatments available and dominated the market for the better part of the 20th century. Dosages were adjusted to resolve symptoms and to normalize the basal metabolic rate and/or serum protein-bound iodine level, but thyrotoxic adverse effects were not uncommon. Two major developments in the 1970s led to a transition in clinical practice: 1) The development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay led to the discovery that many patients were overtreated, resulting in a dramatic reduction in thyroid hormone replacement dosage, and 2) the identification of peripheral deiodinase-mediated T4-to-T3 conversion provided a physiologic means to justify l-thyroxine monotherapy, obviating concerns about inconsistencies with desiccated thyroid. Thereafter, l-thyroxine monotherapy at doses to normalize the serum TSH became the standard of care. Since then, a subgroup of thyroid hormone-treated patients with residual symptoms of hypothyroidism despite normalization of the serum TSH has been identified. This has brought into question the inability of l-thyroxine monotherapy to universally normalize serum T3 levels. New research suggests mechanisms for the inadequacies of l-thyroxine monotherapy and highlights the possible role for personalized medicine based on deiodinase polymorphisms. Understanding the historical events that affected clinical practice trends provides invaluable insight into formulation of an approach to help all patients achieve clinical and biochemical euthyroidism.

Figure. Events influencing the evolution of treatment trends in hypothyroidism

Initial strategies for thyroid hormone replacement included thyroid transplantation, but efficacious pharmacologic strategies soon won favor. Natural thyroid preparations containing T₄ and T₃, such as desiccated thyroid, thyroid extracts, or thyroglobulin, were the initial pharmacologic agents. Synthetic agents were synthesized later. Early clinical trials demonstrated the efficacy of synthetic and natural agents, but concerns arose regarding consistency of natural thyroid preparations and adverse effects associated with T₃-containing preparations (natural or synthetic). With the demonstration of peripheral T₄-to-T₃ conversion and the availability of the serum TSH radioimmunoassay in the early 1970s, there was a major trend in prescribing preference toward l-thyroxine monotherapy. BMR = basal metabolic rate; DT = desiccated thyroid; IV = intravenous; RIA = radioim-munoassay; T₃ = triiodothyronine; T₄ = thyroxine; TG = thyroglobulin; TSH = thyroid-stimulating hormone.