Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes

Thyroid hormone (TH) is crucial for normal development and metabolism of virtually all tissues. TH signaling is predominantly mediated through binding of the bioactive hormone 3,3′,5-triiodothyronine (T3) to the nuclear T3-receptors (TRs). The intracellular TH levels are importantly regulated by transporter proteins that facilitate the transport of TH across the cell membrane and by the three deiodinating enzymes. Defects at the level of the TRs, deiodinases and transporter proteins result in resistance to thyroid hormone (RTH) syndromes. Compounds with thyromimetic potency but with different (bio)chemical properties compared to T3 may hold therapeutic potential in these syndromes by bypassing defective transporters or binding to mutant TRs. Such TH analogues have the potential to rescue TH signaling. This review describes the role of TH analogues in the treatment of RTH syndromes. In particular, the application of 3,3′,5-triiodothyroacetic acid (Triac) in RTH due to defective TRβ and the role of 3,5-diiodothyropropionic acid (DITPA), 3,3′,5,5'-tetraiodothyroacetic acid (Tetrac) and Triac in MCT8 deficiency will be highlighted.