Hypothyroidism brain development

The above-mentioned facts form the basis of a new concept of the adverse effects of not only maternal hypothyroidism, but also maternal hypothyroxinemia without overt hypothyroidism, on fetal brain development. This concept focuses on the necessity for therapeutic correction of maternal hypothyroxinemia detected in pregnancy. MRS, a quantitative laboratory and imaging technique, may be used to show the effects of hypothyroxinemia due to iodine deficiency and its correction in the human brain in an objective manner. 

Historically, clinical and experimental work has focused on the role of thyroid hormones in postnatal brain development. This led to the institution of mandatory neonatal screening to rapidly identify and treat infants with congenital hypothyroidism (Klein et al, 1991), which occurs in approximately 3000-4000 live births. 

Iodine deficiency is the most preventable cause of mental retardation. The food produced in iodine-deficient areas fails to provide sufficient iodine intake, resulting in reduced production of the thyroid hormone thyroxin, which is critical for brain development (Bernal et ai, 2003). Depending on its severity, iodine deficiency affects mental and physical development up to the most severe form of hypothyroidism and cretinism. 

Abnormalities in specific regions of the cerebral cortex and its corticospinal projections, associative cortex and myelination are likely to contribute to neurological impairments in both rats and humans afflicted with hypothyroid disorders. However, although these findings provided us with information about the role ofTH in brain development, they do not provide insight into the developmental timing of TH action on specific brain areas that may underlie the aforementioned observations in children. 

The role of TH is the coordination of seemingly unrelated maturation processes. TH can influence these processes only temporarily during overlapping windows of development with regional specificity. Studies of clinical thyroid disorders and experimental models show that the timing of TH deficiency produces different effects, as illustrated in Figure 108.3 (Zoeller and Rovet, 2004). Furthermore, it is important to confirm the precise time when the THs critical point of activity in brain development occurs, such as the rate of cell division or cell death at specific times in the development of the cerebellum, in order to prevent the irreversible neurological deficits of hypothyroidism in childhood. 

Figure 2. Changes in the rate of in vitro microtubule assembly during brain development. Hiese rates were measuored for the guinea-pig a species v ch has a mature brain at birth and the rat and mouse vMch develop their brain postnatally. Hie figure also shows that the changes in the rates of microtubule assembly is delayed for the hypothyroid rat brain.

Animal models in the marmoset and the sheep have been developed to study the effect of severe iodine deficiency on brain development. Both these models are characterised by the production of severe maternal and fetal hypothyroidism which is associated with effects on the maturation of the cerebral cortex and cerebellum. There was a reduced brain weight with a reduced number of cells as indicated by reduced DNA, a greater density of cells in the cerebral cortex and reduced cell acquisition in the cerebellum. 

N. Kochupillai, M.M. Godbole, C.S. Pandav, A. Mithal and M.M.S. Ahuja, Environmental iodine deficiency, neonatal chemical hypothyroidism (NCH) and iodized oil prophylaxis, 331 "Iodine nutrition, thyroxine and brain development", N. Kochupillai, M.G. Karmakar and V. Ramalingaswami eds., Tata McGraw-Hill Publ., New Dehli (1986), pp. 87-93. 

A related development is the tremendous expansion of neuroscience. Thyroid hormones occupy a central place in brain development. It seems pertinent to bring the neurobiological effects of thyroid hormone disorder to the attention of the neuroscience community, especially as hypothyroidism affects nerve cell growth and connectivity, neurotransmitter levels, membrane functions, and other areas of neurobiology. 

G18 Gomez, O. J., Duvilanski, B. H., Soto, A. M. and Gugliel-mone, A. F. Hormonal regulation of brain development. VI. Kinetic studies of the incorporation in vivo of PH] orotic acid into RNA of brain subcellular fractions of 10-day-old normal and hypothyroid rats. Brain Res., 44,231-243 (1972)... 

Hypothyroid women frequently have anovulatory cycles and are therefore relatively infertile until restoration of the euthyroid state. This has led to the widespread use of thyroid hormone for infertility, although there is no evidence for its usefulness in infertile euthyroid patients. In a pregnant hypothyroid patient receiving thyroxine, it is extremely important that the daily dose of thyroxine be adequate because early development of the fetal brain depends on maternal thyroxine. In many hypothyroid patients, an increase in the thyroxine dose (about 30-50%) is required to normalize the serum TSH level during pregnancy. Because of the elevated maternal TBG levels and, therefore, elevated total T4 levels, adequate maternal thyroxine dosages warrant maintenance of TSH between 0.5 and 3.0 mll/L and the total T4 at or above the upper range of normal. 

The most significant of the abnormalities observed in a hypothyroid brain is a hypoplastic neuropile, i.e., a marked reduction in the number of connections between neurons [102], This has been observed both in the cerebrum and the cerebellum. For instance a permanent and dramatic reduction in the arborization of the dendritic tree of the Purkinje cell is observed in the hypothyroid cerebellum [103]. The length of the primary dendritic trunk is increased and a deficit in the number, density and branching of the dendritic spines is noticed. In contrast neonatal hyperthyroidism accelerates development of spines. Similar findings have been reported for the cerebrum, i.e., reduction in length and branching of pyramidal neurons, of the density of axonal terminals and of the number of spines [102],... 

Thyroxine is critical for the developing human brain and it is likely to be compromised whether serum T4 levels are reduced through transient hypothyroxinemia, with a contribution from iodine deficiency, or from transient hypothyroidism caused by iodine excess. 

It is evident that variations in thyroid hormone levels are among the main physiological modulators of in vivo cellular oxidative stress. The hypermetabolic state in hyperthyroidism is associated with increases in free radical production and lipid peroxidation (LP), and the hypomet-abolic state in hypothyroidism is generally associated with a decrease in free radical production and LP in most tissues (Fernandez et ai, 1985 Venditti et ai, 1997). The development of a hyperthyroid state in vertebrates leads to enhancement of their basal metabolic rate due to an increase in the rate of O2 consumption in most tissues, excluding the spleen, testis and adult brain (Barker and Klitgaard, 1952). Thyroid hormones were shown... 

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