Thyroid hormone metabolism and action in the brain and pituitary

Brain and pituitary development, maturation, and function critically depend on thyroid hormone availabilty. The identification of several forms of nuc lear T3-receptors, the region-specific expression of deiodinase isoenzymes in brain and pituitary, and the molecular analysis of thyroid hormone-respo nsive genes in fetal, newborn, and adult brain opened a new era in the unde rstanding of thyroid hormone action. These integrated networks of receptors , deiodinases, and thyroid hormone responsive genes require strict regulati on of thyroid hormone concentration at the right place and the appropriate time. Knockout and transgenic mouse models of components involved in hypoth alamus-pituitary-thyroid-periphery-feed- back 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, expres sion of mutant thyroid receptors is worse than lack of wildtype receptors. Thyroid hormones control several genes in the CNS and are also essential fo r differentiation of pituitary lactotrophs and somatotrophs. Apart from mos t T3 effects which are mediated by nuclear receptors, T4 itself as well as its lower iodinated metabolites exert direct biological effects in the brai n by mechanisms not involving nuclear T3-receptors.