Iodine deficiency induces multiple intrathyroidal autoregulatory changes leading to an increased triiodothyronine (T₃) production and secretion, at the expense of thyroxine (T₄). It is characterized by low serum T₄, normal or slightly elevated T₃, and as a consequence of the latter, normal thyrotropin (TSH). Tissues are also hypothyroxinemic, but their T₃ concentrations are mostly normal and ensure clinical euthyroidism, except for those that depend to a high degree on local generation from T₄ by extrathyroidal mechanisms involving the iodothyronine deiodinases isoenzymes. Thus, unless iodine deficiency is so severe and chronic that intrathyroidal and extrathyroidal mechanisms are no longer sufficient to maintain a normal T₃ in most tissues, individuals are clinically and biochemically euthyroid, but some tissues may be selectively hypothyroid (i.e., the brain). In adults both the intrathyroidal and the extrathyroidal mechanisms reacting to the iodine deficiency are fully operative even when the latter is mild. They contribute jointly to the maintenance of elevated or normal T₃ in those tissues deriving most of it from the plasma, until iodine deficiency becomes very severe. Those depending to a large extent from local generation from T₄, mostly by an interplay between type 2 iodothyronine deiodinase (D2) and type 3 (D3), may already be T₃-deficient (and hypothyroid) with mild iodine deficiency. Therefore, thyroid status of the iodine-deficient individual not only depends on the degree of iodine shortage, but is mostly tissue-specific, and is difficult to define for the individual as a whole: elevated, normal, and low concentrations of T₃ are found simultaneously in different tissues of the same animal, even with severe deficiencies. Most effects of iodine deficiency are reversed in the adults with an adequate iodine prophylaxis, but the absence of T₄ during early fetal life leads to irreversible brain damage (neurologic cretinism). Thyroid hormones of maternal origin are available to the embryo early in development and continue contributing to fetal thyroid hormone status, even after onset of fetal thyroid secretion. In the case of congenital hypothyroidism and normal maternal T₄, the transfer of the latter, together with increased D2 activity, protects the fetal brain from T₃ deficiency, even when it may be insufficient to maintain euthyroidism in other fetal tissues. Practically all of the T₃ found in the fetal brain is derived locally from T₄, and not from circulating T₃. In the case of severe iodine deficiency, both the embryo and the mother are T₄-deficient; therefore, the fetal brain is exposed to T₃-deficiency, both before and after onset of fetal thyroid function. This leads to irreversible alterations and damage to the central nervous system (i.e. abnormal corticogenesis). Moreover, because intrathyroidal autoregulatory mechanisms are not yet operative in the fetus, both T₄ and T₃ continue to be very low until birth, and the fetus is not only hypothyroxinemic, similar to its mother, but also clinically and biochemically hypothyroid.