Thyroxine, also known as tetraiodothyronine or “T4” for short is an endogenous prohormone released from the follicular cells of the thyroid gland. T4 is converted into the more potent T3 (triiodothyronine) by enzymes called deiodinases. T4 is active on its own but is about 1/3 as potent as T3. Thyroid hormones affect nearly every area of function in the body from a cellular level, from heart rate and metabolism and body temperature to regulation of growth. T3 and T4 release is stimulated by thyroid-stimulating hormone or TSH, which is released from the pituitary. The amount of circulating T3 and T4 is self-limiting through a simple feedback system, whereby increases in thyroid hormones result in decreases of TSH from the pituitary. T4 is primarily transported in a protein-bound fashion, bound mainly to thyroxine-binding globulin and also to serum albumin. T4 was first synthesized in 1927.
As Gromakova writes, “[in the rat] hyper- and hypothyroidism exerted opposite effects on protein synthesis in rats: stimulation and inhibition, respectively.” However, thyroid hormone increases also increase protein breakdown, so net protein synthesis does not increase from hyperthyroidism – in fact, depending on dietary conditions, quite the opposite can occur.
Wiersinga’s analysis of the available data is that T4 is safer and has enough advantages over T3 that T4 should be preferentially used in thyroid hormone replacement therapy (HRT):
Liothyronine (T(3)) has the same drawback and requires twice-daily administration in view of its short half-life. Synthetic levothyroxine (L-T(4)) has many advantages: in view of its long half-life, once-daily administration suffices, the occasional missing of a tablet causes no harm, and the extrathyroidal conversion of T(4) into T(3) (normally providing 80% of the daily T(3) production rate) remains fully operative, which may have some protective value during illness. Consequently, L-T(4) is nowadays preferred, and its long-term use is not associated with excess mortality. The mean T(4) dose required to normalize serum thyroid stimulating hormone (TSH) is 1.6 microg/kg per day, giving rise to serum free T(4) (fT(4)) concentrations that are slightly elevated or in the upper half of the normal reference range.
Clyde writes that while, T4 is an effective treatment for primary hypothyroidism, T4 combined with T3 does not offer any advantages over T3 therapy alone:
Compared with levothyroxine alone, treatment of primary hypothyroidism with combination levothyroxine plus liothyronine demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a HRQL questionnaire, and standard measures of cognitive performance.
Ma et al found minor advantages in combined T3 and T4 vs T4-exclusive treatment, but still stand behind the typical T4-exclusive recommendation for the general population of thyroid HRT patients:
Standard therapy for patients with hypothyroidism is replacement with synthetic thyroxine (T4). However, thyroxine plus triiodothyronine (T3) replacement therapy resulted in marked improvements in several items of the Profile of Mood States and in a few indices of psychometric function and quality of life…. . In conclusion, on the basis of data from recent studies, we conclude that combined T4 and T3 treatment does not improve well-being, cognitive function, or quality of life compared with T4 alone. T4 alone may be beneficial in improving psychological or physical well-being. According to the current evidence, T4 alone replacement may remain the drug of choice for hypothyroid patients.