T4 (commercial name Synthroid), also called thyroxine, is a synthetic version of the endogenous prohormone and active thyroid hormone released by the thyroid gland, tetraiodothyronine. Thyroid hormone replacement therapy with T4 is the standard of care for hypothyroidism. Physiologically, T4 converts to the 3-fold more potent T3 through enzymatic action. Compared to T3, T4 circulates longer and provides a more stable therapeutic blood level with a single daily dose.
Although thyroxine (T4) monotherapy is the accepted standard of care for hypothyroidism, a meta-review found that a combination therapy (liothyronine and levothyroxine, or T3 and T4) is preferred by many patients, and in some cases the metabolic profile is further improved by this combination:
Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T₄:free T₃ ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T₃ available for binding to T₃ receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.
Compared to liothyronine (T3) monotherapy, thyroid blood levels in levothyroxine monotherapy remain stable on a single daily dose, which makes it more convenient for patient compliance:
the difference in the mean SD50 for the two T3 regimens indicates that a single daily dose of oral T3 does not exert a constant biologic effect throughout the day. Thus, because of individual variation and, in the case of T3, because of changing activity during the day a given dose of thyroid hormone may have a widely varying biologic effect.
The functions of the hypothalamus, pituitary, and thyroid collectively comprise the “hypothalamic-pituitaric-thyroid axis,” a feedback loop control system that is activated when blood levels of thyroid hormones (triiodothyronine and tetraiodothyronine) drop sufficiently to “alert” the hypothalamus (through lack of bound TR-beta2 receptors) of low thyroid levels. This triggers release of thyrotropin releasing hormone (TRH) from the hypothalamus; in response, the pituitary releases thyrotropin or thyroid stimulating hormone (TSH), and the thyroid then releases thyroid hormones, primarily tetraiodothyronine (T4). T4 is physically active and capable of suppressing TSH (a diagnostic test used to assess effectiveness of replacement therapy) by itself in hypothyroid subjects; through peripheral enzymatic action (deiodination), most T4 is converted to the 3-fold more powerful T3.
Hypothyroidism can occur at the “secondary” or “tertiary” level of the hypothalamic-pituitaric-thyroid axis (in the pituitary or hypothalamus, respectively) due to organic damage or illness, but most cases are due to an under-functioning thyroid; iodine deficiency or excess and autoimmune thyroid problems are the most common causes.
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