Thyroid hormone metabolism and action in the brain and pituitary

Brain and pituitary development, maturation, and function critically depend on thyroid hormone availability. The identification of several forms of nuclear T3-receptors, the region-specific expression of deiodinase isoenzymes in brain and pituitary, and the molecular analysis of thyroid hormone-responsive genes in fetal, newborn, and adult brain opened a new era in the understanding of thyroid hormone action. These integrated networks of receptors, deiodinases, and thyroid hormone responsive genes require strict regulation of thyroid hormone concentration at the right place and the appropriate time. Knockout and transgenic mouse models of components involved in hypothalamus-pituitary-thyroid-periphery-feedback regulation revealed that lack of thyroid hormone (such as during iodine deficiency) leads to defects and phenotypes other than lack of thyroid receptor(s). In many aspects, expression of mutant thyroid receptors is worse than lack of wild-type receptors. Thyroid hormones control several genes in the CNS and are also essential for differentiation of pituitary lactotrophs and somatotrophs. Apart from most T3 effects which are mediated by nuclear receptors, T4 itself as well as its lower iodinated metabolites exert direct biological effects in the brain by mechanisms not involving nuclear T3-receptors.