**4. Maternal-fetal thyroid in hypothyroid state**

THs are important for growth and differentiation of a variety of organs, including the brain. In developing brain, THs stimulate and coordinate processes such as neuronal proliferation, migration, growth of axons and dendrites, synapse formation and myelination [1,2]. Disturbance of these processes leads to abnormalities in the neuronal network and may result in mental retardation and other neurological defects, including impaired motor skills and visual processing [115]. If TH deficiency occurs at the perinatal stage, such as in congenital hypothyroidism, timely treatment may rescue most of the symptoms. A shortage of THs starting at the early stages of pregnancy, such as in cretinism, results in neurological deficits that cannot be rescued by exogenous TH addition at later stages [25].

136 Thyroid Hormone

There also are reports of nongenomic effects on cell structure proteins by THs. Actin depolymerization blocks DII inactivation by T4 in cAMP-stimulated glial cells, suggesting that an intact actin cytoskeleton is important for this downregulation of deiodinase activity [9,97]. Interestingly, T4, but not T3, can promote actin polymerization in astrocytes [98] and thus may influence the downregulation of DII activity by a secondary mechanism, perhaps by targeting to lysosomes [9,99]. Moreover, the regulation of actin polymerization and F-actin contents also could contribute to the effects of TH on arborization, axonal transport, and cell-cell contacts during brain development, where the regulation of these factors is fundamental for the organization of guidance molecules such as laminin on the astrocyte plasma membrane and modulates integrin–laminin interactions [3]. T4 was required for integrin clustering and attachment to laminin by integrin in astrocytes [100]. These data suggest that the non-genomic

THs are essential for normal neonatal development in both humans and rodents [3,23,101-104] and the experimental work indicated that THs are transported from the mother to the fetus, albeit in limited amounts, and that the fetal brain is exposed to THs before initiation of fetal TH synthesis [1]. In addition, the maternal TH regulates early fetal brain development in human and animal models [2]. The TH of maternal origin can cross the placenta and reach the fetus [2,105,106] and that TRs are expressed in the fetal rat brain before the onset of fetal thyroid function [107]. Thus, the THs are essential for brain maturation from early embryonic stages onward [103,104,108]. However, TH-dependent stages of fetal brain development remain to be characterized. Notably, the maternal thyroid is the only source of T4 and T3 for the brain of the fetus because its thyroid gland does not start contributing to fetal requirements until midgestation in man, and days 17.5–18 in rats [109]. Therefore, the amount of maternal T4 that the fetus receives early in pregnancy will determine TH action in its brain because it depends on maternal T4 for its intracellular supply of the active form of the hormone, T3. However, fetal brain total T3 levels are low (ca. 100 pM) at this time [1], but receptor occupancy approximates 25% since free T3 concentrations are high in the nucleus relative to the cytosol [110]. In general, materno-fetal transfer of THs has been demonstrated in early fetal stages [111] and continues, at least in the case of fetal inability, to produce sufficient TH until term [44]. Actually, brain cells can protect themselves against higher fetal T4 and T3 values by decreasing DII and increasing DIII activity [2]. Taken together, thyroid activity undergoes many changes during normal pregnancy including [1,112-115]: (a) a significant increase in serum thyroxine-binding globulin, thyroglobulin, total T4, and total T3; (b) an increase in renal iodide clearance; and (c) stimulation of the thyroid by human chorionic gonadotropin (hCG).

These changes can make diagnosis of thyroid dysfunction during pregnancy difficult.

THs are important for growth and differentiation of a variety of organs, including the brain. In developing brain, THs stimulate and coordinate processes such as neuronal proliferation, migration, growth of axons and dendrites, synapse formation and myelination [1,2].

**4. Maternal-fetal thyroid in hypothyroid state** 

action may play an important role in promoting the normal development.

**3. Maternal-fetal thyroid in normal state** 

The role of THs in brain development has been studied most extensively in the cerebellum [23,116]. The cellular proliferation and migration processes are disturbed by TH deficiency as investigated predominantly in rodents, where most of cerebellar maturation occurs in the early postnatal period [2]. In the hypothyroid cerebellum, the number and length of Purkinje cell dendrites is severely reduced [1]. At the same time the granule cell parallel fiber growth is reduced, leading to a reduction in axodendritic connections between the Purkinje cells and the granule neurons [117]. Additionally, other cell types such as astrocytes, Golgi epithelial cells, basket cells, and oligodendrocytes show abnormalities under hypothyroid conditions [116]. Several TH target genes have been identified over the years, including genes coding for myelin proteins, cytoskeletal proteins, neurotrophins and their receptors, transcription factors, and intracellular signaling proteins [118] and recent transcriptome analyses continue to increase their number [119-121]. Some of these genes only respond to thyroid status for a short and specific period during development, a feature that is typical for many TH target genes in brain [122]. Interestingly, a reduction or absence of TH during brain maturation yields molecular, morphological and functional alterations in the cerebral cortex, hippocampus and cerebellum [123-132].
