Endocrine Abstracts

The binding of T3 to its nuclear receptors (TR) triggers T3 signaling, modulating the expression of thousands of genes. These events are reversible and fluctuate according to the T3 levels. In developing tissues, T3 signaling also modifies chromatin folding, permanently affecting gene expression throughout life. Hypothyroidism occurs when, at any time, there is insufficient T3 signaling, frequently due to low plasma thyroid hormone levels. The treatment is with levothyroxine (LT4) at doses that normalize serum thyrotropin (TSH) levels. This is because we trust that the deiodinases activate T4 to T3, thus restoring T3 signaling and clinical euthyroidism. This has not been established through randomized clinical trials, but the vast majority of the well-controlled LT4-treated patients seem to remain asymptomatic. Nonetheless, there is evidence that treatment with LT4 does not restore thyroid hormone homeostasis. LT4-treated patients exhibit about 25% higher serum T4 and 5-6% lower serum T3 levels, which is likely to impair T3 signaling in tissues that depend on plasma T3 for their supply of thyroid hormone. We know little about T3 signaling in the brain of LT4-treated patients, only that defects in the deiodinases might further compromise T3 actions. This could explain why some LT4-treated patients (10-20%) exhibit residual symptoms (cognitive, mood, and metabolic deficits, impairment in psychological well-being and quality of life), despite having normal serum TSH levels. It is not clear what makes some patients susceptible to residual symptoms, but the relative deficiency of T3 has justified the addition of LT3 to therapy with LT4. A score of clinical trials concluded that both therapies are safe and equally effective (neither is superior), but patients prefer combination therapy. There is also increasing evidence that a specific subgroup of symptomatic LT4-treated patients benefit from combination therapy. They should be the focus of future clinical trials.