Fetal Tissues Are Exposed to Biologically Relevant Free Thyroxine Concentrations during Early Phases of Development

Abstract

Maternal hypothyroxinemia in early pregnancy is often associated with irreversible effects on neuropsychomotor development. To evaluate fetal tissue exposure to maternal thyroid hormones up to midgestation, we measured total T(4) and free T(4) (FT(4)), T(3), rT(3), TSH, and possible binding proteins in first trimester coelomic and amniotic fluids and in amniotic fluid and fetal serum up to 17 wk. Samples were obtained before interruption of maternal-fetal connections. The concentrations in fetal compartments of T(4) and T(3) are more than 100-fold lower than those in maternal serum, and their biological relevance for fetal development might be questioned. We found, however, that in all fetal fluids the concentrations of T(4) available to developing tissues, namely FT(4), reach values that are at least one third of those biologically active in their euthyroid mothers. FT(4) levels in fetal fluids are determined by both their T(4)-binding protein composition and the T(4) or FT(4) in maternal serum. The binding capacity is determined ontogenically, is independent of maternal thyroid status, and is far in excess of the T(4) in fetal fluids. Thus, the availability of FT(4) for embryonic and fetal tissues would decrease in hypothyroxinemic women, even if they were euthyroid. A decrease in the availability of FT(4), a major precursor of intracellular nuclear receptor-bound T(3), may result in adverse effects on the timely sequence of developmental events in the human fetus. These findings ought to influence our present approach to maternal hypothyroxinemia in early pregnancy regardless of whether TSH is increased or whether overt or subclinical hypothyroidism is detected.

Iodine deficiency and brain development in the first half of pregnancy

“…Second, and equally dangerous, is the reliance on changes in foetal and cord serum TSH values as indicators of foetal thyroid hormone status. The high foetal TSH concentrations reported by Thorpe-Beeston et al 27 and later observed by us 25 4 concentration, because the TSH/fT 4 ratio was constant. The negative correlation that would be expected if the TSH levels were regulated through the hypothalamic-pituitary -thyroid feedback loop was definitely excluded (personal communication by the authors).…”

An ontological view of the human embryo. A paradigm

“…This transference has been extensively confirmed in the rat system of development (29)(30)(31)(32)(33)(34)(35). This hormone is transferred from the mother to the embryo through the placenta at a certain stage of the development of the embryo and is detected in the embryo before the embryo can express its own hormone.…”

Placental Transport of Thyroid Hormone and Iodide

“…These TH levels, expressed as a percentage of corresponding maternal levels in early pregnancy, are shown in Figure 3. Although fetal total T 4 is only about 5% of maternal levels and CF and AF levels are less than 1% of maternal values, free T 4 levels are much higher (approaching maternal levels) in these compartments due to very low TBG levels (Calvo et al 2002). (Calvo et al 2002)).…”

“…There is now clear evidence of THs in fetal serum, coelomic and amniotic fluid and brain in early pregnancy, a time when the fetal thyroid gland has not yet developed the capacity to secrete TH (Calvo, et al 2002). These studies were done in human tissues obtained from fetuses as early as 5-6 weeks gestation.…”

“…It is clear that maternal TH crosses the placenta, entering the human embryonic cavities and fetal blood well before the fetal thyroid is secreting its own TH (Calvo et al 2002;Contempre B 1993) (Figure 3). Total T 4 was detectable in several sets of CF fluid obtained between 5.8 and 11 weeks gestation, with set means ranging from 950 to 1280 pmol/litre.…”