Thyroid hormone replacement has been the mainstay of treatments for hypothyroidism since the 19th century. Animal thyroid preparations, which contain thyroxine (T4) and tri-iodothyronine (T3), were the first pharmacotherapies, and synthetic agents—eg, levothyroxine (also known as LT4)—are the current standard of care. 1 Chemical composition of hormone replacement therapy is important in view of the clinical data suggesting that levothyroxine monotherapy does not consistently normalise serum T3 concentrations1 or universally restore clinical euthyroidism. Although the clinical significance is not clear, increasing serum T3 with a combination of levothyroxine plus liothyronine (also known as LT3) results in weight loss and improves psychological function in some patients. 1 Before 1970, the predominant treatment for hypothyroidism was desiccated thyroid, typically porcine, given at doses to resolve symptoms and normalise the basal metabolic rate and serum proteinbound iodine concentration. 2 Thyrotoxic side-effects were not uncommon, but were remediable by dose reduction; patients with residual hypothyroid symptoms were not routinely reported. Although the efficacy of desiccated thyroid was inconsistent and the costs of levothyroxine had fallen, desiccated thyroid remained the preferred agent because concerns had arisen that levothyroxine monotherapy resulted in a relative T3 deficiency. 2

In the 1970s, the therapeutic approach changed after the development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay, 3 which showed that typical doses (200–400 μg per day of levothyroxine) 2 were supratherapeutic, and the discovery that most circulating T3 is derived via extrathyroidal conversion of