Late maternal hypothyroidism alters the expression of Camk4 in neocortical subplate neurons: a comparison with Nurr1 labeling.

Maternal thyroid hormones (THs) are essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. This is particularly relevant for preterm children who are deprived of maternal THs following birth, are at risk of suffering hypothyroxinemia, and develop attention-deficit/hyperactivity disorder. Expression of neocortical Ca(2+)/calmodulin kinase IV (Camk4), a genomic target of thyroid hormone, and nuclear receptor-related 1 protein (Nurr1), a postnatal marker of cortical subplate (SP) cells, was studied in euthyroid fetuses and in pups born to dams thyroidectomized in late gestation (LMH group, a model of prematurity), and compared with control and developmentally hypothyroid pups (C and MMI groups, respectively). In LMH pups, the extinction of heavy Camk4 expression in an SP was 1-2 days delayed postnatally compared with C pups. The heavy Camk4 and Nurr1 expression in the SP was prolonged in MMI pups, whereas heavy Camk4 and Nurr1 expression in layer VIb remains at P60. The abnormal expression of Camk4 in the cortical SP and in layer VIb might cause altered cortical connectivity affecting neocortical function.

Enfermedades frecuentes del tiroides en la infancia / No disponible

La aparición de alteraciones de la función tiroidea en los niños es muy frecuente. Parece que hay datos suficientes para asegurar que el seguimiento de las hormonas tiroideas, al menos durante la infancia, es muy útil para evitar posibles problemas a largo plazo. Por tanto, cualquier beneficio potencial sería mayor que los posibles efectos dañinos. En los controles de salud de los niños, siempre debe investigarse la presencia de signos de sospecha de disfunción endocrinológica. En esta especialidad tan vinculada a los procesos de crecimiento y desarrollo, donde los signos de casi todas sus patologías son muy discretos en su comienzo, debe agudizarse al máximo la observación, ya que es importante el diagnóstico precoz para que los tratamientos resulten eficaces y puedan evitar las secuelas de la enfermedad. Solo si se investiga, la mayoría de las enfermedades endocrinológicas pueden ser descubiertas tempranamente. Únicamente el pediatra puede contribuir al diagnóstico precoz. La interpretación de normalidad/anormalidad del proceso de crecimiento y desarrollo del niño, es una herramienta de gran utilidad durante la infancia. En la etapa de estudio, así como en la de tratamiento, una vez confirmada la enfermedad, el pediatra debe integrar el equipo ampliado de atención del niño. El pediatra por su parte, en estrecha comunicación con el grupo especializado, conducirá a la familia y al paciente en su nueva condición de enfermo crónico(AU)

The appearance of alterations of the thyroid function in children is very frequent. It seems that there are sufficient data to assure that the control of thyroid function during childhood is at least very useful in order to avoid possible problems in the long-term development. Therefore, any potential benefit would be greater than the possible harmful effects. In the controls of the well child, the signs of suspicion of endocrinologic disfunción must be investigated always. In the processes of growth and development, where the signs of almost all their impairments are very discreet in their beginning, the observation must become thorough since early diagnosis is important for the treatments to be effective and to be able to avoid the sequels of the disease. Pediatricians have an important contribution to the early diagnosis. The interpretation of normality/abnormality of the process of growth and development of the infant, is a very useful tool during childhood. In the stage of study as well as in the treatment, pediatricians must integrate the extended team of childcare. Pediatricians will lead the family and the patient in its new condition of chronic patient(AU)

Metabolismo de las hormonas tiroideas y el yodo en el embarazo / Thyroid hormone and iodine metabolism in pregnancy

El yodo es un micronutriente esencial necesario para que la glándula tiroides sintetice 2 hormonas yodadas: la tetrayodotironina (tiroxina, T4) y la 3’,3,5-triyodotironina (T3), con 4 y 3 átomos de yodo respectivamente. Son necesarias durante toda la vida, especialmente la T4 para el desarrollo de la corteza cerebral, desde el primer trimestre del embarazo. La necesidad de un aporte adecuado de yodo se reconoce entre los Derechos de la Infancia, ya que su deficiencia es, después de la inanición extrema, la causa nutricional más frecuente de retraso mental prevenible en el mundo. Aquí desarrollamos varios puntos: ¿son equivalentes la T4 y la T3 para el cerebro en desarrollo?; ¿qué ocurre con la T4 en condiciones de yodo deficiencia?; ¿qué cambios impone el feto mismo a la función tiroidea de la madre?; ¿qué ocurre cuando hay yodo deficiencia durante el embarazo?; ¿y la lactancia? Contestarlos explica por qué se duplican las necesidades de yodo desde el comienzo mismo del embarazo. Incluso en situaciones de yodo deficiencia leve-moderada, prevalentes todavía en España, se requiere la suplementación diaria con al menos (..) (AU)

Iodine is an essential micronutrient without which the thyroid is unable to synthesize and secrete its two iodine-containing hormones, tetra-iodo-thyronine or thyroxine (T4) and 3’, 3, 5-tri-iodothyronine (T3),containing, respectively, 4 and 3 iodine atoms per molecule. Both hormones are needed throughout life, with T4 being especially important for the development of the cerebral cortex as early as during the first trimester of pregnancy. The need for adequate iodine intake is recognized among the Rights of the Child, since, after starvation, iodine deficiency is the most frequent nutritional cause worldwide of preventable mental retardation. The present article discusses several questions: are T4and T3 equivalent for the developing brain? What happens to T4 during iodine deficiency? What changes are imposed on maternal thyroid function by the fetus? What happens when a pregnant woman is iodine deficient? What effect does breastfeeding have on iodine status? The answers to the above questions explain why iodine requirements are doubled from the very onset of pregnancy. Even in conditions of mild-moderate iodine deficiency, which still prevail throughout Spain, daily supplementation of at least (..) (AU)

Deficiencia de yodo y prematuridad / Iodine deficiency and prematurity

El yodo es un oligoelemento esencial para la síntesis de hormonas tiroideas. La deficiencia de este oligoelemento es especialmente preocupante en el recién nacido, que debe sintetizar suficientes hormonas tiroideas para hacer frente a sus necesidades hormonales, ya que los preparados para alimentación de neonatos a término y prematuros no siempre contienen el yodo necesario. En el mundo, la mayor causa dehipotiroxinemia es la deficiencia de yodo, la cual está reconocida como la causa más importante de retraso mental y parálisis cerebral prevenible (AU)

Iodine is a trace element essential for the synthesis of thyroid hormones. Iodine deficiency is especially worrying inneonates, who must synthesize sufficient thyroid hormones to meet their hormonal requirements, since formula preparations for premature and term infants do not always contain adequate iodine. Worldwide, the main cause of hypothyroxinemia is iodine deficiency, which in turn is the main preventable cause of mental retardation and cerebral palsy(AU)

Ontogenesis of thyroid function and interactions with maternal function.

Fetal and neonatal development of thyroid function involves the embryogenesis, differentiation and maturation of the thyroid gland, of the hypothalamic-pituitary-thyroid axis and of the systems controlling thyroid hormone metabolism. We focus here on aspects related to neurodevelopment. Throughout gestation, thyroxine (T4) transferred from the mother, present in embryonic fluids by 4 weeks, protects the fetal brain. Free T4 (FT4) in fetal fluids increases rapidly, approaching adult levels by midgestation, in concentrations that are determined by the maternal serum T4. T3 remains very low throughout pregnancy. In the cerebral cortex T3, generated from T4, reaches adult values by midgestation and is partly bound to specific nuclear receptor isoforms. The iodothyronine deiodinases are important for the spatial and temporal presence of T3 in different fetal brain areas. After onset of fetal thyroid secretion at midgestation, maternal transfer of T4 continues to contribute importantly to fetal serum T4, protecting neurodevelopment until birth. In rats, even a transient period of maternal hypothyroxinemia disrupts neurodevelopment irreversibly, supporting epidemiological evidence for its negative role in human neurodevelopment. The prompt treatment of maternal hypothyroidism or hypothyroxinemia should mitigate negative effects on neurodevelopment. Neurodevelopmental deficits of preterm infants might also result from an untimely interruption of the maternal transfer of T4 [Morreale de Escobar et al: J Clin Endocrinol Metab 2000;85:3975-3987; Best Pract Res Clin Endocrinol Metab 2004;18:225-248; Eur J Endocrinol 2004;151(suppl 3):U25-U37].

El yodo durante la gestación, lactancia y primera infancia. Cantidades mínimas y máximas: de microgramos a gramos / Iodine during pregnancy, lactation and infancy. Minimum and maximum doses: From micrograms to grams

Una deficiencia de yodo durante el período fetal y posnatal puede dar lugar a déficit de desarrollo mental y psicomotor, tanto más graves cuanto mayor sea la deficiencia de yodo y cuantos antes se haya padecido. Muchos déficit se han hecho irreversibles antes de la mitad de la gestación, por lo que hay que asegurar una ingesta adecuada de yodo (250-300 μg/día) mediante medidas de suplementación desde el comienzo del embarazo. Preferiblemente desde antes de su comienzo.Por elevada que sea la ingesta basal de yodo de la mujer la suplementación diaria con 250-300 μg de yodo no resulta nociva para la madre, el feto ni para el lactante.Hay un amplio margen de seguridad de dos a tres órdenes de magnitud entre las cantidades de yodo beneficiosas durante la gestación y primera infancia y las que pueden ser nocivas. Estas últimas son 500 a 3.000 veces superiores a las que se ingieren habitualmente, incluso cuando se toman suplementos. Las cantidades nocivas de yodo se relacionan invariablente con el uso de medicamentos, de antisépticos yodados (p. ej., povidona yodada) o de medios de contraste radiológicos. No hay actualmente excusa alguna para seguir usando antisépticos que, aunque normalmente inocuos en el adulto, son muy peligrosos durante el embarazo, parto y postparto. Su uso debe quedar terminantemente prohibido, sobre todo considerando que pueden ser sustituidos con eficacia por otros preparados no yodados, como clorhexidina al 0,05%. No debe olvidarse que el feto y el neonato, sobre todo si prematuro, carecen aún de los mecanismos de autorregulación tiroidea del adulto. Como consecuencia, ante un exceso de yodo se produce un un bloqueo del tiroides del feto y del neonato, sobre todo cuando éste es prematuro. Este hipotiroidismo iatrogénico puede dar lugar a defectos irreversibles de maduración cerebral, ya las consecuencias serían las mismas que las que se observan en niños con hipotiroidismo congénito, que no se han tratado a tiempo con tiroxina

An insufficient iodine intake during fetal and postnatal development often results in disorders of mental and psicomotor development, which are the more severe, the greater the degree of iodine deficiency and the earlier it is suffered during development. Many of these disorders have become irreversible by midgestation, and it is necessary to ensure the mother with an intake of 250- 300 μg I/day, from the beginning of the pregnancy or, preferably, before its onset, and throughout lactation. When the pregnancy is planned, supplementation ought to start before conception.Even if the basal iodine intake of the pregnant woman is more than adequate, supplementation with 250- 300 μg I/day is safe for her, the fetus and the newborn.There is a great margin of safety between the amounts of iodine which are beneficia, and those which are dangerous, as the latter are 2 to 3 orders of magnitude higher than the former. The amounts of iodine which may be harmful are 500-3,000 times higher than those we receive through food, even when dietary supplements are added. Harmful doses of iodine are invariably associated with the use of some medicines and drugs, mainly of iodinated disinfectants, or of radiological contrast agents. The damage results from the lack of maturation in fetuses and neonates, of thyroid autorregulatory mechanisms that protect the adult thyroid from the blocking effects of an iodine excess. There is at present no excuse for not totally banning, completely and permanently, the use of such disinfectants, especially during delivery, and the newborn period. Other disinfectants, such a clorhexidine, are equally effective without increasing the risk of inducing iatrogenic hypothyroidism during important phases of human brain development. It should continuously be born in mind that thyroid failure of the fetus and newborn, especially if preterm, may result in irreversible brain damage, whether its cause, is congenital or iatrogenic

Yodo y embarazo / Iodine and pregnancy

No disponible

Dynamics and regulation of intracellular thyroid hormone concentrations in embryonic chicken liver, kidney, brain, and blood.

The intracellular thyroid hormone (TH) availability is influenced by different metabolic pathways. We investigated the relationship between tissue and plasma TH levels as well as the correlation with changes of deiodination and sulfation during chicken embryonic development. From day 14 until day 19, T3 remains unchanged in liver and kidney in spite of increasing plasma T4 and T3 levels and a slightly increased T4 availability in these tissues. During this period, the T3 breakdown capacity by type III deiodinase (D3) is high in liver but low in kidney. The TH inactivation capacity of type I deiodinase (D1), with production of inactive rT3 instead of T3, in kidney seems to be potentiated by the sulfation pathway. A sharp rise in T3 and T4 is detected in all tissues examined when the embryo switches to lung respiration. The same day, T4 content in liver is sharply enhanced and sulfation activity is decreased. So, T4 availability in liver is increased while a declined D3 activity allows for the accumulation of hepatic T3. The increase in renal T3 and T4 are more closely related to plasma TH profiles and a lack of correlation with the changes in renal D1 and D3 activity suggests that T4 and T3 content in this organ is strongly dependent on direct uptake from the blood. Despite much lower T4 levels, T3 levels in brain are in the same range as in liver and kidney and intracellular T3 even exceeds the T4 levels towards the end of development. The rise in TH content coincides with a drop in D3 activity, low sulfation activity and an increased T3 production capacity via type II deiodinase (D2). In conclusion, the current study describes the dynamics of intracellular TH concentrations in liver, kidney, and brain during chicken development and investigates their relationship with circulating TH levels and changes of deiodinases and sulfotransferases. The clear differences in intracellular TH profiles among the different tissues demonstrate that circulating levels are not necessarily representative for the local TH changes. Some of the changes in intracellular TH availability can be linked to changes in local deiodination and sulfation capacities, but the importance of these enzyme systems in relation to other factors, such as hormone uptake, differs between liver, kidney, and brain.

Thyroid hormone distribution in the mouse brain: the role of transthyretin.

Transthyretin is the major thyroxine-binding protein in the plasma of rodents, and the main thyroxine-binding protein in the cerebrospinal fluid of both rodents and humans. The choroid plexus synthesizes transthyretin and secretes it to the cerebrospinal fluid. Although it was suggested that transthyretin might play an important role in mediating thyroxine transfer from the blood into the brain across the choroid plexus-cerebrospinal fluid barrier, newer findings question this hypothesis. Because thyroid hormone passage across brain barriers is a precondition for its action in the CNS, and because brain is an important target of thyroid hormone action, we investigated the role of transthyretin in mediating thyroid hormone access to and distribution within the brain in a transthyretin-null mouse model system. In this report we describe the results derived from use of film autoradiography, a technique that yields definitive morphological results. Film autoradiograms were prepared at 3 and 19 h after intravenous injection of either high specific activity [(125)I]thyroxine or [(125)I]triiodothyronine. Image analyses were designed to demonstrate regional changes in hormone distribution, and to highlight alterations in iodothyronine delivery from ventricles to brain parenchyma. We find no qualitative or quantitative differences in these parameters between the transthyretin-null and the wild-type mouse brain after either [(125)I]thyroxine or [(125)I]triiodothyronine administration. The data presented here now provide definitive evidence that, under standard laboratory conditions, transthyretin is not required for thyroid hormone access to or distribution within the mouse brain. This study also provides the first map of iodothyronine distribution in the brain of the mouse.

Audiogenic seizure susceptibility in thyroid hormone receptor beta-deficient mice.

As early-onset hypothyroidism produces audiogenic seizure susceptibility (AGS) in rodents, the role of TR alpha 1 and TR beta thyroid hormone receptors in AGS was investigated. AGS occurs in mice lacking specifically TR beta (Thrb(tm1/tm1)) and is marked by early onset and persistence, thereby differing from mouse strains where AGS is age-restricted. Thrb(tm1/tm1) mice display AGS whether on a mixed 129/Sv x C57BL/6J or congenic C57BL/6J background. 27% of wild-type mice on the mixed and 0% on the congenic background exhibited AGS. The inability of Thrb(tm1/tm1) mice to downregulate the response to sustained acoustic stimulation may reside in the brain or in the auditory system itself as Thrb(tm1/tm1) mice also display auditory deficits. The AGS phenotype identifies a novel neurological role for TR beta.

The role of thyroid hormone in fetal neurodevelopment.

Thyroid hormones are necessary for normal brain development during fetal and postnatal life. The stage at which the central nervous system becomes thyroid hormone sensitive, however, has not been clearly defined. There is increasing evidence from epidemiological studies and patient reports that these hormones are already needed for orderly development during the first trimester, when the fetus is entirely dependent on the maternal transfer of thyroxine, the main substrate for intracellular generation of the more active 3,5,3'-triiodothyronine for binding to the nuclear hormone receptors. A decrease in maternal circulating thyroxine during the first trimester, whether or not accompanied by increased circulating thyroid-stimulating hormone, may well result in irreversible mental and psychomotor impairments. The very frequent cause of this is an iodine intake insufficient to meet the requirements of the pregnant woman. It appears urgent to ensure the use of iodine supplements from before or very early in pregnancy, and to screen all women for hypothyroxinemia as early as possible. Maternal thyroxine continues to be important for the exposure of fetal tissues to adequate amounts of this hormone during the second and, possibly, the third trimesters. Premature birth, which interrupts this transfer, results in neonatal hypothyroxinemia. This is more severe the earlier it occurs during development, and is an important cause of the poorer mental and neuromotor development of many preterm infants. The possibility of supplying them with thyroxine during the neonatal period is being seriously tested.

Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?

Several recent publications have drawn attention to the role of the thyroid hormone status of the mother on the future neuropsychological development of the child. The screening of pregnant women for clinical or subclinical hypothyroidism based on second trimester elevated maternal TSH values has been proposed. Here, we have summarized present epidemiological and experimental evidence strongly suggesting that conditions resulting in first trimester hypothyroxinemia (a low for gestational age circulating maternal free T4, whether or not TSH is increased) pose an increased risk for poor neuropsychological development of the fetus. This would be a consequence of decreased availability of maternal T4 to the developing brain, its only source of thyroid hormone during the first trimester; T4 is the required substrate for the ontogenically regulated generation of T3 in the amounts needed for optimal development in different brain structures, both temporally and spatially. Normal maternal T3 concentrations do not seem to prevent the potential damage of a low supply of T4, although they might prevent an increase in circulating TSH and detection of the hypothyroxinemia if only TSH is measured. Hypothyroxinemia seems to be much more frequent in pregnant women than either clinical or subclinical hypothyroidism and autoimmune thyroid disease, especially in regions where the iodine intake of the pregnant woman is inadequate to meet her increased needs for T4. It is proposed that the screening of pregnant women for thyroid disorders should include the determination of free T4 as soon as possible during the first trimester as a major test, because hypothyroxinemia has been related to poor developmental outcome, irrespective of the presence of high titers of thyroid autoantibodies or elevated serum TSH. The frequency with which this may occur is probably 150 times or more that of congenital hypothyroidism, for which successful screening programs have been instituted in many countries.

El yodo durante la gestación, lactancia y primera infancia. Cantidades mínimas y máximas: de microgramos a gramos / Iodine during pregnancy, lactation and infancy. Minimun and maximum doses: from micrograms

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Tissue-specific patterns of changes in 3,5,3'-triiodo-L-thyronine concentrations in thyroidectomized rats infused with increasing doses of the hormone. Which are the regulatory mechanisms?

We have measured 3,5,3'triiodothyronine (T3) in 12 tissues from thyroidectomized (Tx) rats infused with increasing doses of T3, and related them to their corresponding plasma levels. Young adult Wistar rats were surgically Tx. After 4 weeks, the animals were infused with placebo or T3 (0.25, 0.50, 0.75, 1.00 or 2.00 microg/100 g body weight/day). Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, cerebellum, brown adipose tissue (BAT), pituitary, liver, heart, lung, kidney, spleen, skeletal muscle, ovary and adrenal were obtained after 12-13 days of infusion. We determined plasma T3 and thyrotropin (TSH), and tissue T3 and thyroxine (T4), the latter being virtually undetectable. Results were compared with the relationships between tissue and plasma T3 in Tx rats on T4 infusions. Most tissues presented changes which paralleled those in plasma T3, irrespective of its source (infusion of T3, or generation from infused T4). However, at similar plasma T3 concentrations, cerebral cortex, cerebellum and BAT (containing type II 5' iodothyronine deiodinase (DII) activity), reached much lower T3 levels in the T3-infused Tx rats, than in Tx rats on T4, and required elevated plasma T3 levels for normal tissue T3. In these tissues, and in the pituitary, T3 concentrations were always lower than expected from plasma T3 levels. On the contrary, the lung and ovary of the T3-infused Tx rats contained more T3 than expected from plasma T3. Unexpectedly, both the ovary and adrenal attained higher tissue T3 concentrations in Tx rats on T3 than on T4 at comparable plasma T3 levels. In conclusion, the patterns of changes of the concentrations of T3 as a function of increasing plasma T3 are not only tissue-specific when T4 is provided, but also when circulating T3 is the only source of this iodothyronine. Further studies are needed to identify the mechanisms involved in the regulation of tissue T3 concentrations.

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8.

Keratins K8 and K18 are the major components of the intermediate-filament cytoskeleton of simple epithelia. Increased levels of these keratins have been correlated with various tumor cell characteristics, including progression to malignancy, invasive behavior, and drug sensitivity, although a role for K8/K18 in tumorigenesis has not yet been demonstrated. To examine the function of these keratins, we generated mice expressing the human K8 (hk8) gene, which leads to a moderate keratin-content increase in their simple epithelia. These mice displayed progressive exocrine pancreas alterations, including dysplasia and loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. Histological changes were not observed in other simple epithelia, such as the liver. Electron microscopy showed that transgenic acinar cells have keratins organized in abundant filament bundles dispersed throughout the cytoplasm, in contrast to control acinar cells, which have scarce and apically concentrated filaments. The phenotype found was very similar to that reported for transgenic mice expressing a dominant-negative mutant TGF-beta type II receptor (TGFbetaRII mice). We show that these TGFbetaRII mutant mice also have elevated K8/K18 levels. These results indicate that simple epithelial keratins play a relevant role in the regulation of exocrine pancreas homeostasis and support the idea that disruption of mechanisms that normally regulate keratin expression in vivo could be related to inflammatory and neoplastic pancreatic disorders.

Thyroid hormones in human tumoral and normal nervous tissues.

We have studied T4 and T3 concentrations, DNA and protein concentrations and 5' and 5 deiodinases in samples of brain tumors obtained at surgery from 49 patients, and, in most cases, also from surrounding normal tissue. T4 concentrations in normal cortical tissue (6.19+/-0.45 ng/g) were lower than in white matter, but the difference disappeared when referred to the DNA content (2.26+/-0.27 ng/mg DNA). No other differences were found between cortical and white matter, or among cortical lobes. T4 in normal tissue was higher than previously reported, mostly from autopsy samples, whereas T3 (0.99+/-0.07 ng/g) was similar. 5'D-I activity was negligible as compared to 5'D-II (8.11+/-1.09 fmol/h/mg protein). When expressed in relation to the different DNA contents of normal vs. tumoral tissue, 5'D-II activities were the same for both. 5D activity was highly variable in the tumoral tissue, with negligible activities in meningiomas and pituitary adenomas. When referred to the DNA content, T4 and 5'D-II were the same, but T3 concentrations were lower in the tumor (0.24+/-0.03 ng/mg DNA) as compared to normal (0.35+/-0.04 ng/mg DNA) tissue samples. Whether or not this decrease of T3 affects the expression of T3-sensitive processes remains to be studied.