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)

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

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.

Myelin basic protein immunoreactivity in the internal capsule of neonates from rats on a low iodine intake or on methylmercaptoimidazole (MMI).

Rats fed on low iodine diets (LIDs) result in a normal circulating level of triiodothyronine (T3), a low level of thyroxine (T4) and an elevated thyroid-stimulating hormone (TSH). These changes are similar to those observed in habitants who live in iodine-deficient areas and different from those observed when the hypothyroidism is produced by goitrogens. To study the effects of LID or goitrogens on the myelin basic protein (MBP) immunoreactivity (MBP-ir) during the myelination of the internal capsule, one group of experimental female rats was fed on an LID, and another group received a standard laboratory diet with methylmercaptoimidazole (MMI) added in the drinking water. Animals fed on a standard laboratory diet and animals fed on an LID supplemented with KI were used as controls. At P10, the MMI treatment has produced a more marked decrease in the surface density of MBP-ir processes with respect to controls than that produced in the LID animals. This decrease was correlated with the cerebral concentrations of triiodothyronine (T3) we found. During the postnatal development, a recovery in the levels of the surface density with respect to controls was observed in both experimental groups. The recovery occurred by P20 in the LID group and by P32 in the MMI rats.

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

The most severe brain damage associated with thyroid dysfunction during development is observed in neurological cretins from areas with marked iodine deficiency. The damage is irreversible by birth and related to maternal hypothyroxinemia before mid gestation. However, direct evidence of this etiopathogenic mechanism is lacking. Rats were fed diets with a very low iodine content (LID), or LID supplemented with KI. Other rats were fed the breeding diet with a normal iodine content plus a goitrogen, methimazole (MMI). The concentrations of -thyroxine (T4) and 3,5,3'triiodo--thyronine (T3) were determined in the brain of 21-d-old fetuses. The proportion of radial glial cell fibers expressing nestin and glial fibrillary acidic protein was determined in the CA1 region of the hippocampus. T4 and T3 were decreased in the brain of the LID and MMI fetuses, as compared to their respective controls. The number of immature glial cell fibers, expressing nestin, was not affected, but the proportion of mature glial cell fibers, expressing glial fibrillary acidic protein, was significantly decreased by both LID and MMI treatment of the dams. These results show impaired maturation of cells involved in neuronal migration in the hippocampus, a region known to be affected in cretinism, at a stage of development equivalent to mid gestation in humans. The impairment is related to fetal cerebral thyroid hormone deficiency during a period of development when maternal thyroxinemia is believed to play an important role.

Outer ring iodothyronine deiodinases and thyroid hormone economy: responses to iodine deficiency in the rat fetus and neonate.

Female rats were fed a low iodine diet (LID) or the same diet supplemented with KI (IOD) and mated. Plasma TSH, T4 and T3 in thyroid, plasma, and tissues, and 5'-deiodinase activities (5'D) were measured in maternal, fetal, and neonatal samples. Plasma T4 was markedly reduced in LID dams, TSH was increased, and T3 was normal. Placental T4 was decreased to 10%, and placental T3 to 50%. In LID fetuses there was a complete depletion of both extrathyroidal and intrathyroidal stores of T4 and T3. The thyroid responded with increased synthesis and secretion of T3 over T4, as assessed from the T3 to T4 ratios. Near birth, brain T4 and T3 concentrations were only 6.7% and 12% of those in IOD fetuses, despite a marked increase in brain 5'D-II and a T4-sparing decrease in liver and lung 5'D-I. Brown adipose tissue 5'D-II increased 7-fold, and brown adipose tissue T4 and T3 concentrations were only decreased by 50%. After birth, the availability of iodine improved somewhat through maternal milk, and the thyroidal and extrathyroidal pools of T4 and T3 increased, although they remained much lower than those in IOD pups. Brain 5'D-II markedly increased in LID pups, and this together with an increase in plasma and brain T4 ensured almost normal brain T3 during the suckling period. The thyroidal secretion of T3 over T4 continued to be increased in LID pups during the suckling period and appeared to be related to their high circulating TSH levels. Both LID fetuses and newborns can respond to iodine deficiency as adults rats, but the fetus is more sensitive to LID because of its dependence on maternal T4. The success of the adaptative mechanisms in protecting the brain from severe T3 deficiency depends on the supply of iodine, the limiting factor for the synthesis of T4.

Generalized deficiency of 3,5,3'-triiodo-L-thyronine (T3) in tissues from rats on a low iodine intake, despite normal circulating T3 levels.

Rats fed a low iodine diet have decreased total and nuclear T3 concentrations in the liver and brain, as compared with rats supplemented with iodine, possibly because of the very low plasma and tissue T4 pools in low-iodine diet rats, leading to decreased intracellular generation of T3 in those tissues. If so, T3 levels should not decrease in heart and skeletal muscle, as plasma T3 is normal in low-iodine diet rats and these two tissues derive their intracellular T3 directly from plasma T3. We have studied this point in male rats fed a low-iodine diet, a low-iodine diet + iodine, and the stock diet. As in previous studies, low-iodine rats had very low plasma T4 and high plasma TSH levels, plasma T3 levels being normal. Liver T3 decreased, and so did the brain T3 levels despite a compensatory increase in type II 5' iodothyronine deiodinase activity. Contrary to expectations, T3 concentrations were lower in the heart and skeletal muscle of low-iodine diet rats. Attempts to clarify the possible mechanism(s) involved have been unsuccessful so far. The present results show that, despite normal plasma T3, a deficiency of T3 occurs in more tissues of rats on a low iodine intake than previously assumed. If the present results are pertinent to inhabitants from areas with severe iodine deficiency, it would appear that they might suffer from a generalized tissue T3 deficiency (and hypothyroidism?), even if overt clinical signs are not usually present.

Effects of maternal iodine deficiency on thyroid hormone economy of lactating dams and pups: maintenance of normal cerebral 3,5,3'-triiodo-L-thyronine concentrations in pups during major phases of brain development.

Female rats were fed a diet with a low iodine content (LID), or the same LID supplemented with KI, and mated. Fetuses were obtained at 17 and 21 days of gestation, or pups were killed at different ages after birth. The dams on LID were markedly iodine deficient and developed a large goiter. Their thyroidal iodine content was only 4% of that of LID + I dams. The iodine deficiency of the LID mothers was severe enough to result in very low plasma T4 levels and in hepatic and cerebral T3 deficiency, despite normal circulating levels of T3. The fetuses from LID dams had low concentrations of iodine in their placentas and thyroid glands, and were deficient both in T4 and T3 in all tissues studied, including the brain. After birth, however, suckling LID pups were able to increase the plasma T4 to levels which were higher than those found in either LID fetuses or in adult LID progeny, although plasma T4 was always lower than in age-paired LID + I animals. This increase in T4 was probably due to an approximately 5-fold increase in iodine intake while suckling. Milk from LID mothers was found to contain 22% of the amount of iodine found in milk from LID + I dams, in contrast to their iodine intake, which was about 4% that of the LID + I rats. Cerebral T3 levels were the same for LID and for LID + I pups throughout most of the postnatal period of brain development. This finding might explain the difficulties encountered in obtaining an experimental model of neurological cretinism in rats.

Effects of maternal iodine deficiency on the L-thyroxine and 3,5,3'-triiodo-L-thyronine contents of rat embryonic tissues before and after onset of fetal thyroid function.

Female rats were placed on a low iodine diet (LID) or LID supplemented with KI. They were mated 3-6 months later. Maternal and embryonic tissues were obtained both before the onset of fetal thyroid function, at 11 and 17 days of pregnancy, and at 21 days of gestation. T4 and T3 concentrations were measured by RIA. T4 concentrations were very low in the plasma, liver, and lung of LID dams and in all embryonic samples obtained from such mothers, namely 11-day-old embryotrophoblasts, 17-day-old placentas and embryos, 21-day-old placentas, embryos, plasma, liver, lung, and carcass (whole embryos minus the trachea, thyroid, blood, liver, and brain). T3 was low in 17-day-old placentas and embryos and in all fetal tissues obtained at 21 days of gestation from LID dams. These results show that when iodine deficiency is severe enough to result in very low maternal plasma T4 levels, embryonic tissues are deficient in T4 and T3 both before and after the onset of fetal thyroid function. This finding might be relevant to the etiopathology of human iodine deficiency disorders.

Cerebral hypothyroidism in rats with adult-onset iodine deficiency.

Rats fed chronically a low iodine diet may have low serum T4 and high circulating TSH, despite normal serum T3. As the brain depends to a great extent on intracellular generation of T3 from T4 for its total and nuclear T3, we have carried out two experiments to determine whether the brain of iodine-deficient rats may become hypothyroid, despite normal serum T3 levels. In both experiments we confirmed previous data, showing that the pituitary and liver of iodine-deficient rats with very low plasma T4 levels are hypothyroid as compared to those of animals receiving the same diet supplemented with KI, though not as markedly as animals which had undetectable circulating levels of both T4 and T3 as a consequence of chronic ingestion of KC1O-4, or of surgical thyroidectomy. We have further found that the nuclear T3 content was decreased in the brain of iodine-deficient rats, as compared with the animals on the iodine-supplemented diet. The nuclear to plasma ratios of labeled T3 showed that the uptake of this hormone into liver and brain nuclei is not decreased in the iodine-deficient rats as compared with those on the iodine-supplemented diet. This finding indicates that the decreased liver and brain nuclear T3 contents of iodine-deficient rats are likely to be a consequence of the marked reduction of their T4 pool, leading to decreased amounts of intracellularly generated T3. The number of spines on shafts of pyramidal neurons from the visual cortex of iodine-deficient rats was lower than that of rats fed the same diet supplemented with KI. Their distributions along the shaft were also not the same. Such changes might well be an index of cerebral hypothyroidism, as they are similar to those found after thyroidectomy of adult rats. It is concluded from the present findings that normal circulating T3 levels may not be sufficient to maintain brain euthyroidism in rats fed a diet iodine deficient enough to result in very low circulating T4 levels.