**2.1 Intracellular T3 supply**

Circulating concentrations of both T4 and T3 along with target tissue uptake of the same and local activation or inactivation determine the intracellular supply of T3 (the active hormone). The thyroid gland secretes the pro-hormone T4 in larger proportions which is converted to the active form T3 in the liver and kidney through deiodination of T4 by type 1 iodothyronine deiodinase enzyme (DIO1). A major part (around 90%) of the circulating thyroid hormone remains bound to plasma proteins, and the concentration of free T3 (fT3) exceeds that of free T4 (fT4) by three to four times [13, 14].

There are specific membrane transporters associated with target tissue uptake of thyroid hormones; considered as monocarboxylate transporters (MCT8, MCT10), and organic acid transporter protein-1c1 (OATP1C1) [15]. Activity of T3 inside the cell is regulated by DIO2 and DIO3, as DIO2 converts T4 to T3 and DIO3 blocks the activation of T3 by producing reverse T3 [16].

Thyroid hormones mediate their actions through interaction with thyroid receptors (TRs). Unbound TRs bind with corepressor proteins and bind with thyroid response elements located at the promoter regions of the target genes and suppress transcription. Once thyroid hormone binds with its receptor, the receptor undergoes a conformational change with the unbinding of the corepressor proteins and facilitation of gene transcription following binding with the thyroid response elements at the target genes [14–16].
