F. Escobar Del Rey

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].

Rapid effects of adult-onset hypothyroidism on dendritic spines of pyramidal cells of the rat cerebral cortex.

SummaryWe have previously shown (Ruiz-Marcos et al. 1980, 1982) that thyroidectomy (T) performed in rats at 40 days of age, well past the neonatal period of development, results by 80–90 days of age in a decrease of the number of spines along the shaft of pyramidal neurons with the cell body in layer V in the visual area of the cerebral cortex. We have here studied how soon after the operation an effect on spine number and distribution may be observed. We have found that the response of these neurons to T is very rapid: a decrease in the number of spines/shaft between T and age-paired controls (C) rats is statistically significant by the earliest period of observation, namely 5 days after T. These results may be related to those of Dembri et al. (1983) showing that T performed in adult rats decreases the activity of Type I RNA polymerase by 5 days after the operation. It is possible that T impairs the synthesis of some compound(s) necessary for the formation and maintenance of spines. The present results suggest that spine number is not a fixed structure of the apical shaft once brain development is over, but is in a state of continuous formation and degradation. We have further observed that the effect of T performed at 40 days of age is more pronounced in the distal part of the shaft than on the rest, a result similar to that found after neonatal T (Ruiz-Marcos et al. 1982). However, contrary to findings after early hypothyroidism, T at 40 days of age does not distort the distribution of spines along the shaft.

Differential effects of thyroid hormones on growth and thyrotropic hormones in rat fetuses near term.

We have studied the effects of thyroid hormone deficiency and excess on GH and TSH economy in the rat fetus near term. Pregnant rats were either left untreated (C group) or treated with methimazole to block thyroid function and infused with placebo, T4, T3, or both, until 21 days of gestation. Two experiments were performed: the doses (per 100 g body wt/day) of T4 ranging from 2.4-21.6 micrograms, those of T3 from 1.5-13.5 micrograms, with groups on 2.4 micrograms T4 + 1.5 micrograms T3. Fetal plasma T4 levels varied between 6-160% of C values and T3 values between 52-770%. Both plasma and pituitary GH decreased in hypothyroid fetuses from methimazole dams, and their plasma TSH was elevated. When T4 and/or T3 were infused, plasma and pituitary GH increased as a function of fetal plasma T4 and T3, reaching normal values when plasma T3 levels became normal, then increasing further. The effects on GH economy were related to the plasma T3 level, with no appreciable difference if T3 had been infused or derived from T4. In contrast, the elevated plasma TSH of the hypothyroid fetus decreased toward normal values when fetal plasma levels of T4, and of T3 derived from T4, became normal, but was not affected by normal fetal plasma T3 when T3 was infused. In the absence of T4, T3 decreased plasma TSH only when infused in doses that increased fetal plasma T3 3-fold above C values or more. Thus, both GH and TSH economy are under thyroid hormone control in rat fetuses near term. Similarities and differences with respect to regulation in adult rats cannot, however, be attributed exclusively to differences in fetal somatotrophs and thyrotrophs, because of the possibility that control is exerted at regulatory sites which are unique to the fetus.

Effect of hypothyroidism on the size of spines of pyramidal neurons of the cerebral cortex

We have previously shown that hypothyroidism produces a decrease in the number of spines counted along the apical shafts of pyramidal neurons of the cortex. Nevertheless, other authors have found that when an animal is subjected to some adverse living conditions the size of the spines decreases, making them invisible to the light microscope. The question arises then of whether the decrease in the number of spines reported by us in hypothyroid animals is real or is due to a shrinking effect. In order to elucidate this question the cross-surface area of dendritic spines of apical shafts belonging to 20- and 60-day-old rats, thyroidectomized at 10 days of age, as well as those of their corresponding controls were measured in different layers of their cortex, studied using conventional electron microscopic techniques. The application of the three-way analysis of variance model to these data has shown us that while the age of the animal produces a definite increase in the size of the spines, hypothyroidism does not produce any change in their size, leading us to the conclusion that the decrease in the number of spines previously reported is due to an actual loss of these elements.

EFFECTS OF THYROID HORMONES ON LIVER BINDING SITES FOR HUMAN GROWTH HORMONE, AS STUDIED IN THE RAT

Several weeks after thyroidectomy (t̄), female rats stopped growing, and their pituitary GH content had decreased to less than 2‐3% of the values found for age‐matched controls (C). The liver membranes of such animals were explored with human GH (hGH). It was found that in the severely hypothyroid t̄ rat, the number, but not the affinity, of the lactogenic binding sites was markedly reduced. Treatment of these rats for 3 weeks with 1.75 μg or T4 or 0.5 μg T3/100 g body weight/ day restored growth, increased pituitary GH content and restored the number of liver lactogenic binding sites practically to normal. As regards the lactogenic binding sites, similar results were obtained when the severely hypothyroid rats were treated with a much lower T4 dose (0.2 μg/lOO g/day): this dose was clearly growth promoting, and restored to normal both the low circulating GH levels and the pituitary PRL content of the severely hypothyroid rat. The changes in plasma PRL were not clear. The lactogenic binding sites on liver membranes from rats which were both thyroidectomized and hypophysectomized were decreased in number. Treatment with 0.5 μg T3/100 g/day for 30 days (but not for 12 days) resulted in an increase in the number of lactogenic binding sites, though it did not affect growth or the undetectable plasma CH levels. The effect on the lactogenic binding sites was less marked than in t̄ rats with an intact pituitary. It would appear that minute amounts of thyroid hormones are needed for maintenance of liver lactogenic binding sites; it is possible that this not only occurs through mechanism(s) Correspondence: Prof. S. Duran‐Garcia, Hospital Universitario, Planta 7a, Sevilla, Spain.

El yodo durante la gestación, lactancia y primera infancia. Cantidades mínimas y máximas: de microgramos a gramos

Las hormonas tiroideas, tiroxina (T4) y 3,5,3’-triyodotironina (T3) son necesarias durante todas las fases de la vida para una función normal del sistema nervioso central (SNC). Son especialmente cruciales durante el desarrollo del SNC, pues una insuficiencia de estas hormonas se acompaña de lesiones y defectos neurológicos permanentes e irreversibles. Ambas hormonas contienen yodo, cuatro átomos por molécula en el caso de la T4, tres en el caso de la T3. Sin yodo no es posible su síntesis, a pesar de lo cual a lo largo de la evolución no han aparecido otras hormonas capaces de sustituirlas y que no tengan esta total dependencia de un elemento, que suele encontrarse en cantidades muy pequeñas fuera del ambiente acuático marino. En cambio, ha evolucionado una estructura, el folículo tiroideo, capaz de minimizar las consecuencias de un aporte asaz variable del yodo, obtenido en su mayor parte a través de los alimentos y el agua. Es la única estructura endocrina capaz de almacenar estas hormonas en forma de prohormona (la tiroglobulina), con tal eficacia que un adulto, que ha tenido una nutrición adecuada de yodo, puede hacer frente a las necesidades hormonales de su organismo durante varios meses después de iniciarse un período de carencia total del mismo en su alimentación. A su vez, la glándula tiroides del adulto es capaz de evitar las posibles consecuencias nocivas de la producción de un exceso de hormonas tiroideas, que podrían producirse al llegarle cantidades muy altas de yodo. Si embargo, surgen problemas importantes cuando la deficiencia de yodo en la alimentación se hace crónica, o cuando la exposición a un exceso de yodo es muy prolongada, sobre todo cuando esto ocurre durante un período del desarrollo en que la glándula aún no está plenamente preparada para ello. De no resolverse estos problemas, o de resolverse a destiempo, pueden producirse déficit más o menos graves e irreversibles del SNC. En este breve comentario se intentará definir, con mayor precisión, cuáles son las cantidades mínimas para un desarrollo normal del SNC, y cuáles las que pueden dar lugar a problemas durante el embarazo y primera infancia, períodos en los que tienen lugar en el ser humano fases cruciales de maduración cerebral. Hay, sobre todo con respecto al exceso de yodo, bastantes problemas de índole práctico, tal y como describen con acierto y amplio apoyo bibliográfico Arena y Emparanza en este mismo número1.

Clinical dilemmas arising from the increased intake of iodine in the Spanish population and the recommendation for systematic prescription of potassium iodide in pregnant and lactating women (Consensus of the TDY Working Group of SEEN).

Iodine deficiency is one of themost easily preventable public health problems, but despite that, it still affects a very great number of people worldwide (1). Over half of the European population lives in countries where the iodine intake is insufficient (2, 3). Iodine deficiency in Spain has been recognized since 1899 (4), and has been found in 15 of the 17 autonomous regions of Spain where it has been studied, no information being available in the other 2. In 1980 the Spanish Society of Endocrinology and Nutrition (SEEN) formed a Working Group on Iodine Deficiency Disorders (the TDY Group of the SEEN). This group has actively studied the problem in Spain, bringing it repeatedly to the attention of Public Health authorities and promoting several monographs collecting data from the various studies carried out in Spain on iodine deficiency disorders up to 1993 (5, 6). More recently, 8 scientific societies have joined in a manifesto presented at a meeting held in Malaga, Spain, stressing the need for a more active Public Health policy to eradicate iodine deficiency disorders in Spain (See Appendix). Spain still lacks a national plan for the eradication of iodine deficiency, although certain autonomous regions have undertaken campaigns and put in practice policies to increase the urinary iodine concentration in school-age children and reduce the prevalence of goiter (7). Currently, the national Ministry of Health and the regional ministries are setting up programs to increase the consumption of iodised salt and, as in the case of Andalusia, recommend the prescription during pregnancy and lactation of a preparation containing at least 150 μg of iodine per day (8). Although many multivitamin-mineral preparations that contain different amounts of iodine are sold in Spain, a preparation of potassium iodide (Recordati formulation) has recently been promoted and subsidized by public funding with individual doses of 100 and 200 μg of iodine/tablet (130.8 μg KI and 261.6 μg KI, respectively) that helps implementation of the recommendations of the TDY Group of the SEEN for pregnant and lactating women. This has resulted in the frequent expression of concerns by gynecologists and general practitioners, as well as some specialists in endocrinology and nutrition, about the risks and benefits of the use of iodised salt in the general population and, especially, about the indications and contraindications of potassium iodide supplements during pregnancy and lactation. The aim of this report is to draw up a guideline for good clinical practice by answering dilemmas expressed by the medical community concerning the increasing use of iodine-containing products in the general Spanish population, especially among pregnant women.

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.

Nutrition and iodine versus genetic factors in endemic goiter

Consanguinity has been considered to be the major factor responsible for the high incidence of goiter in the area of Las Hurdes in Spain. However, iodine deficiency was later found to be severe enough to account for endemic goiter, and the presence of cretins in this area. Children from very similar family and socioeconomic backgrounds were found to be on three different nutritional programs, depending on the schools they were attending, and it appearedof interest to determine the effect of nutrition on the goiter incidence in children from the same population. Total iodine, nitrogen and creatinine concentrations were measured in casual urine samples. All three were found to change in parallel in the different subpopulations. They were low in schoolchildren receiving most of their meals at home. Such meals were composed of locally grown food. They were normal in children living in a boarding school, where all of the food is provided from outside the area. They were intermediate in children from a day care center, who received only some meals from an outside source. In the boarding school, goiter incidence was 21%, as opposed to 87% for schoolchildren fed at home. Such results indicate that in this area consanguinity plays a minor role, if any, in the high incidence of goiter.

Metabolismo de las hormonas tiroideas y el yodo en el embarazo. Razones experimentales para mantener una ingesta de yodo adecuada en la gestación

El yodo es un micronutriente esencial necesario para que la glandula tiroides sintetice 2 hormonas yodadas: la tetrayodotironina (tiroxina, T4) y la 3’,3,5-triyodotironina (T3), con 4 y 3 atomos 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, despues de la inanicion extrema, la causa nutricional mas frecuente de retraso mental prevenible en el mundo. Aqui desarrollamos varios puntos: ?son equivalentes la T4 y la T3 para el cerebro en desarrollo?; ?que ocurre con la T4 en condiciones de yododeficiencia?; ?que cambios impone el feto mismo a la funcion tiroidea de la madre?; ?que ocurre cuando hay yododeficiencia durante el embarazo?; ?y la lactancia? Contestarlos explica por que se duplican las necesidades de yodo desde el comienzo mismo del embarazo. Incluso en situaciones de yododeficiencia leve-moderada, prevalentes todavia en Espana, se requiere la suplementacion diaria con al menos 200 μg de yodo, empezando, de ser posible, antes del embarazo y hasta el final de la lactancia.