Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain.

Abstract

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.)

Neonatal Hypothyroxinemia: Effects of Iodine Intake and Premature Birth

“…Mimicking intrauterine conditions by transient postnatal treatment with T 4 might improve some of the thyroidrelated events, such as maturation of thyroidal T 4 and T 3 synthesis. Van den Hove et al (personal communication) observed that treatment of the very premature (24 -32 weeks GA) PT neonates for 3 days or more with 10 g T 4 /kg BW⅐day resulted in increases in the degree of iodination of Tg and the proportion of I found as T 4 and T 3 , to values similar to those in T neonates.…”

“…Although the capacity to synthesize thyroglobulin (Tg), to concentrate iodine (I), and to synthesize T 4 and T 3 may start earlier, secretion of iodinated hormones by the fetal thyroidal is believed to start at midgestation, when hypothalamic-pituitary circulation matures, and TSH is secreted into the fetal blood (4,5). As shown in fetal serum obtained in utero by cordocentesis (6,7), T 4 and free T 4 (FT 4 ) do not clearly increase until 20 -24 weeks gestation, and free T 3 (FT 3 ) is mostly undetectable until after 32 weeks. Thus, the earlier in pregnancy, the more immature the fetal gland and the more important the proportion of fetal requirements that are met by the maternal contribution of hormone.…”

“…Once fetal thyroid secretion starts, fetal supplies are of mixed fetal and maternal origin. Although fetal thyroidal secretion is believed to constitute an increasing proportion of the hormone available to the developing fetus, maternal transfer of T 4 may still contribute significantly to fetal needs (20 -50% of normal values) up until term (2), mitigating the consequences of an inadequate fetal thyroid function (3). Although the capacity to synthesize thyroglobulin (Tg), to concentrate iodine (I), and to synthesize T 4 and T 3 may start earlier, secretion of iodinated hormones by the fetal thyroidal is believed to start at midgestation, when hypothalamic-pituitary circulation matures, and TSH is secreted into the fetal blood (4,5).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…MMI crosses the placenta and has been shown to inhibit fetal thyroidal function and promote severe fetal hypothyroidism with elevated serum TSH and low thyroid hormone levels in blood and tissues. Mothers are treated with thyroid hormone (T 4 , T 3 , or both) and, at any time during pregnancy or immediately after delivery, fetuses are dissected and blood/ tissues obtained for extraction and determination of T 4 and T 3 contents (345,346). Administration of tracer [ 125 I]T 4 to pregnant dams and its detection in fetal tissues has also been used to study placental transfer of thyroid hormone (347).…”

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

“…Pregnant rats were divided into two groups (n=30 in each group). Hypothyroidism was induced in rats using protocols described previously (Calvo et al 1990). Briefly, pregnant dams were given 0·025% 2-mercapto-1-methylimidazole (MMZ) in drinking water ad libitum from gestational day 8.…”