Role of thyroid hormone during early brain development

Best Practice & Research Clinical Endocrinology & Metabolism, 2004

During the last few decades our understanding of the possible role of thyroid hormones during brain development has increased and contributed to resolve previously discordant hypotheses, although much remains to be clarified. Thyroid hormones of maternal origin are present in the fetal compartment, despite the very efficient uterine-placental 'barrier', necessary to avoid potentially toxic concentrations of free T4 and T3 from reaching fetal tissues before they are required for development. T3 remains low throughout pregnancy, whereas FT4 in fetal fluids increases rapidly to adult levels, and is determined by the maternal availability of T4. It is present in embryonic fluids 4 weeks after conception, with FT4 steadily increasing to biologically relevant values. T3, generated from T4 in the cerebral cortex, reaches adult values by mid-gestation and is partly bound to specific nuclear receptor isoforms. Iodothyronine deioidinases are important for the spatial and temporal regulation of T3 bioavailability, tailored to the differing and changing requirements of thyroid hormone-sensitive genes in different brain structures, but other regulatory mechanism(s) are likely to be involved. Maternal transfer constitutes a major fraction of fetal serum T4, even after onset of fetal thyroid secretion, and continues to have an important protective role in fetal neurodevelopment until birth.

Seminars in Perinatology, 2008

This review briefly summarizes: (1) the changes in maternal thyroid function that are imposed by the presence of the fetus and the high concentrations of human chorionic gonadotropin essential for the maintenance of the pregnancy, which result in high first trimester free thyroxine and triiodothyronine, requiring doubling of the iodine intake; (2) the changes in the fetal compartment up to midgestation, which result in increasing concentrations of triiodothyronine in the cerebral cortex generated locally from thyroxine by high activities of type 2 iodothyronine deiodinase; (3) the important role of the maternal contribution of thyroxine to the fetal circulation after onset of secretion of hormones by the fetal thyroid; and (4) the consequences of the interruption of the maternal supply of thyroid hormones that occur with prematurity. Efforts to devise appropriate strategies to avoid or shorten the postnatal hypothyroxinemia of infants born prematurely may well result in fewer and less severe neurodevelopmental deficits. Semin Perinatol 32:380-386

Nutrients

This scoping review critically discusses the publications of the last 30 years on the impact of mild to moderate iodine deficiency and the additional impact of endocrine disrupters during pregnancy on embryonal/fetal brain development. An asymptomatic mild to moderate iodine deficiency and/or isolated maternal hypothyroxinemia might affect the development of the embryonal/fetal brain. There is sufficient evidence underlining the importance of an adequate iodine supply for all women of childbearing age in order to prevent negative mental and social consequences for their children. An additional threat to the thyroid hormone system is the ubiquitous exposure to endocrine disrupters, which might exacerbate the effects of iodine deficiency in pregnant women on the neurocognitive development of their offspring. Ensuring adequate iodine intake is therefore essential not only for healthy fetal and neonatal development in general, but it might also extenuate the effects of endocrine disrupt...

1990

To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase of T3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal "euthyroidism" is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal.

Public Health Nutrition, 2007

An inadequate supply of iodine during gestation results in damage to the foetal brain that is irreversible by mid-gestation unless timely interventions can correct the accompanying maternal hypothyroxinemia. Even mild to moderate maternal hypothyroxinemia may result in suboptimal neurodevelopment. This review mainly focuses on iodine and thyroid hormone economy up to mid-gestation, a period during which the mother is the only source for the developing brain of the foetus. The cerebral cortex of the foetus depends on maternal thyroxine (T 4 ) for the production of the 3 0 ,3,5-tri-iodothyronine (T 3 ) for nuclear receptor-binding and biological effectiveness. Maternal hypothyroxinemia early in pregnancy is potentially damaging for foetal brain development. Direct evidence has been obtained from experiments on animals: even a relatively mild and transient hypothyroxinemia during corticogenesis, which takes place mostly before mid-gestation in humans, affects the migration of radial neurons, which settle permanently in heterotopic locations within the cortex and hippocampus. Behavioural defects have also been detected. The conceptus imposes important early changes on maternal thyroid hormone economy that practically doubles the amount of T 4 secreted something that requires a concordant increase in the availability of iodine, from 150 to 250-300 mg I day 21 . Women who are unable to increase their production of T 4 early in pregnancy constitute a population at risk for having children with neurological disabilities. As a mild to moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia, the birth of many children with learning disabilities may be prevented by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible, in order to ensure that their requirements for iodine are met.

The American journal of clinical nutrition, 1993

Thyroid hormones, thyroxin (T4) and 3,5,3'-triiodothyronine (T3), of maternal origin, are available to the mammalian embryo early in development. However, after the onset of fetal thyroid function, they are of both fetal and maternal origin. Maternal T4 has a protective effect on the fetal brain in cases of congenital hypothyroidism. In severe iodine deficiency, maternal T4 is low, although T3 is normal; the developing embryo is markedly T4-deficient; and T3 deficiency increases with gestational age. In contrast to mechanisms in the hypothyroid fetus from a normal mother, the low T4 of the iodine-deficient mother prevents any protective effects on the fetal brain. Thyroid hormone deficiency of the iodine-deficient fetus, including the brain, is more severe and prolonged than it is in the cases of maternal or fetal thyroid failures. These findings may help to explain the relationship between severe maternal hypothyroxinemia and the severe central nervous system damage of the neur...

Cerebral Cortex, 2010

Hypothyroxinemia affects 35--50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers' organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

JOURNAL OF CLINICAL INVESTIGATION, 1990

To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase of T3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal "euthyroidism" is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal. (J. Clin. Invest. 1990. 86:889-899.)

Thyroid, 2009

T he article by Pere Berbel and his Spanish coworkers, published in this issue of Thyroid (1), is fascinating both for the results reported and its clever study design, unique among all other studies published so far on the consequences of iodine deficiency (ID) during pregnancy. Because this study combines data on specific maternal aspects with information on infant neurodevelopment, the present editorial was written jointly by two authors representing these different disciplines. ID is considered to be one of the most frequent causes of preventable mental retardation in children worldwide. Because ID is now recognized as a major public health issue for both maternal and fetal=child health, micronutrient fortification with dietary iodine has been listed as priority number 3 among 30 proposals that constitute major worldwide challenges for which solutions presently exist. These proposals, entitled ''2008 Copenhagen Consensus,'' have been recently established by a panel of eight of the world's most distinguished economists, including five Nobel laureates (2).

Indian journal of endocrinology and metabolism, 2014

Recent studies have shown that early pregnancy hypothyroxinemia (lower free thyroxin [FT4] and normal thyroid stimulating hormone [TSH] concentration) has deleterious effects on neuro-intellectual development of children. This study was designed to know its incidence in local pregnant women. Urinary iodine (UI) and serum thyroid related hormone (FT4, free triiodothyronine [FT3], and TSH) were determined in 254 pregnant women during the first trimester. UI and thyroid related hormones were determined by colorimetric (Sandell-Kolthoff) and radioimmunoassay method respectively. Most of the pregnant women (n = 202; 79.5%) were iodine deficient (ID; UI <100 μg/L) and only 52 (20.5%) women were taking sufficient iodine (IS; UI ≥ 100 μg/L). Mean levels of FT4, FT3, and TSH were 13.0 ± 2.8 pmol/L, 3.8 ± 1.1 pmol/L and 1.2 ± 1.1 mIU/L, respectively. Maternal FT4 levels were significantly correlated with UI (r = 0.36; P < 0.001). Mean FT4 level in IS women was significantly (P < 0.05...