The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

History of Treatment for Hypothyroidism

Historically, before thyroid hormones were identified, patients with hypothyroidism were treated with ovine thyroid gland extracts. Thyroxine was isolated in 1914 and became clinically available several decades later. Since the 1930s, T4 became the therapy of choice for hypothyroidism. Synthesis of T3 during the 1950s led to the development of combination therapy, which was first used clinically during the 1960s.[27] It was later found that T4 is converted to T3 through peripheral deiodination and that an excess of T3 leads to hyperthyroidism introducing an entirely different set of symptoms (Figure 1).[28] In addition to avoiding the risk for hyperthyroidism, T4 monotherapy is widely used because of its long half-life of (6–7 days) compared to only 2.5 days for T3. The short half-life of T3 results in peak serum levels within 2–4 hours following oral administration[29] and accordingly the need for relatively frequent dosing. With effective peripheral conversion, a low risk of hyperthyroidism, and less frequent dosing, T4 is widely considered a much more convenient and effective therapy for patients.

Figure 1.

Overview of thyroid hormone regulation. Thyroid-releasing hormone (TRH) is synthesized and stored in the paraventricular nuclei in the hypothalamus. TRH stimulates cells in the anterior pituitary gland to release thyrotropin (also known as TSH) into the circulation, where it binds with receptors on cells in the thyroid gland, thereby stimulating the release of thyroid hormone. Both inactive T4, with 4 iodine moieties attached, and T3, with 3 iodine moieties attached, are released as a result of this interaction. As the hypothalamus and pituitary sense that thyroid hormones in the circulation are inadequate, increased amounts of TRH and TSH are secreted. Excessive thyroid hormone has an inhibitory effect (denoted as [-]) on the secretion of TRH and TSH. Circulating T3 and T4 bind primarily with thyroxine-binding globulin (TBG), transthyretin (pre-albumin), and albumin. Inactive T4 is converted to active T3 in the peripheral tissues by iodothyronine deiodinases, which exerts its action on nuclear thyroid hormone receptors.