What are the differences between Thyroxine (T4) and Triiodothyronine (T3)?

From the Guidelines

Thyroxine (T4) and Triiodothyronine (T3) are two distinct thyroid hormones with different functions, potencies, and clinical applications, where T4 serves as a prohormone that is converted to T3 to exert its effects. The primary difference between T4 and T3 lies in their biological potency, with T3 being 3-5 times more potent than T4 1. T4, produced mainly by the thyroid gland, has a longer half-life of 5-7 days compared to T3's shorter half-life of about 1 day. This difference in half-life makes T4 medications, such as levothyroxine, the standard treatment for hypothyroidism, providing stable blood levels and consistent symptom control with once-daily dosing.

Some key differences between T4 and T3 include:

• T4 is the primary hormone produced by the thyroid gland and serves mainly as a prohormone
• T3 is the more active form with greater biological potency
• T4 has a longer half-life compared to T3
• T4 medications are the standard first-line treatment for hypothyroidism due to their stable blood levels and consistent symptom control

The body's natural conversion of T4 to T3 in peripheral tissues through deiodinases is crucial for exerting most of the hormonal effects. While most patients do well on T4 alone, some individuals with persistent symptoms despite normal TSH levels may benefit from combination T4/T3 therapy, as noted in the context of treating thyroid dysfunction 1. However, the USPSTF found no direct evidence that treatment of thyroid dysfunction based on risk level alters final health outcomes, emphasizing the importance of individualized treatment approaches.

Given the current understanding and clinical practices, the use of T4 as the primary treatment for hypothyroidism is recommended due to its stability, efficacy, and the body's natural ability to convert it to T3. T3 medications, like liothyronine, may be considered in specific cases but are not the first-line treatment due to their rapid fluctuations in blood levels and the need for multiple daily doses.

From the FDA Drug Label

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination Table 10. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients Hormone Ratio in Thyroglobulin Biologic Potency t 1/2(days) Protein Binding (%)

• Levothyroxine (T4) 10 to 20 1 6 to 7 ** 99.96
• Liothyronine (T3) 1 4 ≤ 2 99.5

The main differences between Thyroxine (T4) and Triiodothyronine (T3) are:

• Biologic Potency: T4 has a biologic potency of 1, while T3 has a biologic potency of 4.
• Half-life: T4 has a half-life of 6 to 7 days, while T3 has a half-life of less than or equal to 2 days.
• Protein Binding: Both T4 and T3 are highly bound to plasma proteins, but T4 has a higher affinity for these proteins.
• Metabolism: T4 is converted to T3 in peripheral tissues, with approximately 80% of circulating T3 derived from T4.
• Source: T4 is the precursor to T3, with the majority of T3 being derived from T4 by deiodination 2

From the Research

Differences between Thyroxine (T4) and Triiodothyronine (T3)

• Thyroxine (T4) is a prodrug that is converted to Triiodothyronine (T3) in the body, with T3 being the active form of the hormone that acts on target tissues 3, 4
• T4 has a longer half-life compared to T3, which allows for once-daily dosing of levothyroxine (LT4) 5
• The conversion of T4 to T3 is mediated by deiodinase enzymes, and polymorphisms in these enzymes can affect the efficacy of LT4 monotherapy 4, 6
• T3 is not fully restored in LT4-treated patients, and combination therapy with LT4 and liothyronine (LT3) may be beneficial for patients who remain symptomatic on LT4 therapy 3, 7

Pharmacokinetics and Dosage

• The pharmacokinetics of LT4 and T3 differ, making it challenging to co-administer the two hormones 4
• Recommended starting doses for combination therapy are: 100 μg LT4 + 10-12.5 μg LT3; 100 μg LT4 + 7.5-10 μg LT3; and 87.5 μg LT4 + 7.5 μg LT3; for <10%, 10-20%, and >20% residual thyroid function, respectively 5
• Desiccated thyroid extract (DTE) is a form of combination therapy with an LT4/LT3 ratio of ∼4:1, but its use is not formally regulated by the FDA 3

Clinical Implications

• Combination therapy with LT4 and LT3 may be considered for patients who have not benefited from LT4 monotherapy, but the evidence is not yet conclusive 3, 4, 6
• Persistent symptoms in patients who are biochemically euthyroid with LT4 monotherapy may be caused by conditions unrelated to thyroid function, and should be investigated by the clinician 6