Gabriella Morreale de Escobar

Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation.

BACKGROUND Maternal hypothyroxinemia, due to gestational iodine deficiency, causes neurological dysfunctions in the progeny. Our aim was to determine the effects of delayed iodine supplementation (200 microg KI per day) to mildly hypothyroxinemic pregnant women at the beginning of gestation (i.e., having circulating free thyroxine [FT(4)] within the 0th-10th percentile interval and normal thyrotropin [TSH]) on the neurobehavioral development of their children. METHODS Using the Brunet-Lézine scale, we evaluated the neurocognitive performance at 18 months of age in three groups of children. Group 1 included children of women with FT(4) above the 20th percentile at 4-6 gestational weeks and at full-term. Group 2 included children of mildly hypothyroxinemic women diagnosed during the first 12-14 gestational weeks and with FT(4) above the 20th percentile at full-term. Group 3 included children born to mildly hypothyroxinemic women at full-term, without iodine supplementation during gestation. Women of all groups were iodine supplemented from the day of enrollment until the end of lactation. RESULTS Before iodine supplementation, 33.0% of the women (114 out of 345) were hypothyroxinemic, with FT(4) below normal in 28 of them (8.1%). None were found to be hypothyroxinemic at full-term after supplementation. The mean (+/-SD) developmental quotient of children was 101.8 +/- 9.7 in group 1 (n = 13) vs. 87.5 +/- 8.9 in group 3 (n = 19; p < 0.001) and 92.2 +/- 5.4 in group 2 (n = 12; p < 0.05). The difference between groups 2 and 3 was not statistically significant. Delayed neurobehavioral performance was observed in 36.8% and 25.0% of children in groups 3 and 2, respectively, compared with no children in group 1. Differences (p < 0.001) were found on gross and fine motor coordination and socialization quotients. No statistically significant differences were found on language quotients. CONCLUSIONS A delay of 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny. Public health programs should address the growing problem of iodine deficiency among women of gestational age in developing and industrialized nations.

Thyroid hormones influence serum leptin concentrations in the rat.

Leptin, the product of the ob gene, is secreted by adipocytes and has been shown to decrease appetite and increase energy expenditure. Leptin mRNA in adipocytes correlates with body wt, and serum leptin levels correlate with body fat. Alterations in thyroid status are frequently associated with changes in body wt. To evaluate the possible influence of thyroid status on the leptin system, we have measured serum leptin concentrations in thyroidectomized rats infused either with placebo, or with different doses of T4 (0.8 to 8.0 μg/100 g body wt per day) or T3 (0.25 to 2.0 μg/100 g body wt per day), covering a wide range of thyroid hormone concentrations, from overt hypothyroidism to hyperthyroidism. Intact animals infused with placebo were used as euthyroid controls. Infusion of T4 or T3 into thyroidectomized rats resulted in a decrease in serum leptin levels with respect to the thyroidectomized animals infused with placebo. When compared to the control group, serum leptin levels were decreased in the group...

Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: The effects of fetal hypothyroidism and maternal thyroid hormones

ABSTRACT: We have studied the ontogenesis of 5′-deiodinase (5′D) activity in rat brain during fetal life, its capacity to respond to maternal or fetal hypothyroidism, and its regulation by maternal thyroid hormones. Type II 5′D (5′ D-II) activity increases 4-fold during the period studied (17 to 22 days of gestation), mainly between days 19 and 21. Fetal brain T4 concentrations increase in parallel with fetal plasma T4, whereas fetal brain T3 concentrations increase 18 times (days 17–21), six times more than would have been expected from the small increase in fetal plasma T3 levels. Maternal thyroidectomy did not affect 5′D-II activity or thyroid hormone concentrations in fetal brain (except brain T4 at 18 days of gestation). Fetal hypothyroidism, induced by giving a goitrogen (methimazole) to the mothers, depleted all fetal tissues studied, including the fetal thyroid, from thyroid hormones. By 19 days of gestation, the fetal brain was able to respond to hypothyroidism with a 3− to 5-fold increase in 5′D-II activity. Earlier onset of treatment with methimazole led to 2− to 3-fold increases in 5′D already at 17 and 18 days of gestation, showing that when fetal thyroid secretion starts the fetal brain 5′D-II is able to respond to hypothyroidism. Replacement of methimazole-treated mothers with physiological doses of T4, given by constant infusion, increased T4 and T3 concentrations in fetal brain, and inhibited fetal, as well as maternal, brain 5′D-II activity. But treatment of the mothers with T3 did not change T3 concentrations in the fetal brain, despite the increase in fetal plasma T3, and actually increased 5′D-II in fetal brain. Maternal cerebral 5′D-II was not inhibited by T3 treatment. Inverse relationships were found between the 5′D-II and thyroid hormone concentrations in the fetal brain. These correlations were not identical for fetuses from thyroidectomized and control mothers. In fetuses from thyroidectomized dams, brain 5′D-II is more sensitive to a decrease in brain T4 than in the progeny of control dams. The present results describe the developmental changes in rat cerebral 5′D-II activity and its regulation by thyroid hormones. Although fetal plasma T3 is 10% of adult levels, T3 concentrations in fetal brain increase almost to adult levels, suggesting an important role of local T3 production from T4, and thus, of 5′D-II in fetal brain. In addition, brain 5′D-II responds to thyroid hormone deficiency and can be modulated by maternal thyroid hormones when the fetus is hypothyroid.

Thyroid Hormones and the Developing Brain

There are three main situations in which an association has been noted between anomalies of thyroid function and mental retardation: (A) Severe endemic goiter associated since the XVIth century with the birth of deaf-mute and imbecile inhabitants, known as cretins (1). This association was recognized before it was even known that goiter is an enlarged thyroid. (B) Congenital hypothyroidism associated with severe mental retardation since Curling described two cases in the mid-XIXth century (2)

Iodine supplementation during pregnancy: a public health challenge

Iodine deficiency remains the most frequent cause worldwide, after starvation, of preventable mental retardation in children. It causes maternal hypothyroxinemia, which affects pregnant women even in apparently iodine-sufficient areas, and often goes unnoticed because L-thyroxine (T4) levels remain within the normal range, and thyroid-stimulating hormone (TSH) is not increased. Even a mild hypothyroxinemia during pregnancy increases the risk of neurodevelopmental abnormalities, and experimental data clearly demonstrate that it damages the cortical cytoarchitecture of the fetal brain. The American Thyroid Association (ATA) recommends a supplement of 150 microg iodine/day during pregnancy and lactation, in addition to the use of iodized salt. We discuss the importance of iodine supplementation to ensure adequate T4 levels in all women who are considering conception and throughout pregnancy and lactation.

Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence‐derived neurons

Correct positioning of cortical neurons during development depends on the radial migration of the projection neurons and on the coordinated tangential and radial migrations of the subcortically generated interneurons. As previously shown, a transient and moderate maternal deficiency in thyroxin during early corticogenesis alters the radial migration of projection neurons. To determine if a similar effect might also affect tangential migration of medial ganglionic eminence (MGE)‐derived neurons at the origin of cortical interneurons, explants of MGE from green fluorescent protein (GFP)‐transgenic embryos were implanted into flat cortical mounts from wild‐type embryos. The distances covered and the preferential migration (medially) of GFP‐MGE neurons from embryos of hypothyroxinemic dams are not affected in their tangential migration into wild‐type control cortices. In contrast, when GFP‐MGE neurons from embryos of control or hypothyroxinemic dams migrate within cortices from embryos of hypothyroxinemic dams, the GFP‐MGE‐derived neurons lose their preferential direction of migration, although they still migrate for long distances throughout the cortex. Our results show that maternal hypothyroxinemia alters the tangential migration of GFP‐MGE‐derived neurons in the neocortex of the progeny and suggest that this alteration is not derived from the migratory neurons themselves but through undefined short‐ and long‐range cues responsible for the guidance of their migration.

Fetal and Maternal Thyroid Hormones

It is well known that insufficient production of thyroid hormones during the fetal and neonatal period of development may result in permanent brain damage unless treatment with thyroid hormone is instituted very soon after birth. But congenital hypothyroidism is not the only situation in which brain damage may be related to insufficient thyroid function. Cretinism is the most severe manifestation of iodine deficiency disorders found in areas where iodine intake is greatly reduced. Some of the manifestations of cretinism suggest that the insult to the developing brain starts earlier than in the case of congenital hypothyroidism. Hypothyroxinemia of mothers with adequate iodine intake may also leave permanent, though less severe, mental retardation. For these reasons the possible role of maternal transfer of thyroid hormones during early fetal development have been reinvestigated, using the rat to obtain various experimental models. It has been shown that thyroid hormones are found in embryonic tissues before onset of fetal thyroid function and that thyroidectomy of the mother results in delayed development of the concepta. The concentrations of T4 and T3 in embryonic tissues from thyroidectomized dams were undetectable before the onset of fetal thyroid function, and still reduced in some tissues near term, despite the onset of fetal thyroid function. Treatment of control and thyroidectomized dams with methyl-mercaptoimidazole to block fetal thyroid function reduced thyroid hormone concentrations in fetal tissues near term, but this decrease could be partially avoided by infusion of physiological doses of thyroxine to the mothers. Iodine deficiency of the mothers resulted in thyroid hormone deficiency of the developing embryo, which was very marked until term in all tissues including the brain. The results strongly support a role of maternal thyroid hormones in fetal thyroid hormone economy both before and after the onset of the fetal thyroid function, at least in the rat. They also support a role of the hypothyroxinemia of iodine-deficient mothers in initiating the brain damage of the endemic cretin, a damage which would not be corrected once the fetal thyroid becomes active, as iodine-deficiency of the fetus would impair adequate production of hormones by its own thyroid, and maternal transfer would continue to be low.

Regulation of Iodothyronine Deiodinase Activity as Studied in Thyroidectomized Rats Infused with Thyroxine or Triiodothyronine

To provide new insights into the in vivo regulation of iodothyronine deiodinases in the different tissues of the rat, we have evaluated the effects on these enzymatic activities of T4 or T3 infusions into thyroidectomized rats. Thyroidectomized rats were infused with placebo, T4, or T3. Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, brown adipose tissue, pituitary, liver, and lung were obtained after 12–13 days of infusion. Plasma TSH, plasma and tissue T4 and T3, and iodothyronine deiodinase activities were determined. Type II 5′-deiodinase (DII) was increased in cortex, brown adipose tissue, and pituitary from animals infused with placebo. DII activity returned to normal only with T4 infusion, remaining elevated in the animals infused with T3 alone despite normal tissue T3 concentrations. Cortex type III 5-deiodinase was only increased when hyperthyroidism was induced by infusion of T3. Liver type I 5′-deiodinase (DI) paralleled the changes in plasma and...

Generation and Characterization of dickkopf3 Mutant Mice

ABSTRACT dickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation and characterization of dkk3 mutant mice. dkk3-deficient mice are viable and fertile. Phenotypic analysis shows no major alterations in organ morphology, physiology, and most clinical chemistry parameters. Since Dkk3 was proposed to function as thyroid hormone binding protein, we have analyzed deiodinase activities, as well as thyroid hormone levels. Mutant mice are euthyroid, and the data do not support a relationship of dkk3 with thyroid hormone metabolism. Altered phenotypes in dkk3 mutant mice were observed in the frequency of NK cells, immunoglobulin M, hemoglobin, and hematocrit levels, as well as lung ventilation. Furthermore, dkk3-deficient mice display hyperactivity.

The Changing Role of Maternal Thyroid Hormone in Fetal Brain Development

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.