Conjoint Endocrinology Laboratory - Thyroid Hormone Binding Proteins

Placental Thyroid Hormone Transport

Normal fetal neurological development depends on a regulated supply of maternal thyroid hormone and iodide. Fetal thyroid hormone synthesis does not begin until around 12 weeks gestation and is dependent on a supply of maternal hormone until at least that time. A low iodide supply or abnormally low or high levels of maternal thyroid hormone impairs fetal neurological development. However, the mechanisms which control transplacental delivery of thyroid hormone and iodide from mother to fetus are still very poorly understood.

The fetal thyroid gland begins to secrete thyroid hormone at around 16 weeks gestation but before this, fetal development is dependent on maternal thyroid hormone. Maternally derived iodothyronines have been detected in embryonic cavities as early as the second month of pregnancy; studies of earlier stages of pregnancy have not been possible. There is evidence that later in pregnancy, at least in the case of a hypothyroid fetus, transfer of maternal thyroid hormone to the fetus continues. The mechanism and regulation of this is unclear. Using the isolated perfused human placental lobule, we have previously reported very little transfer of T4, unless placental D3 is inhibited, suggesting that deiodination is an important regulatory step. D3, while not expressed in significant amounts in most normal adult tissues is expressed in many fetal tissues such as liver and is particularly highly expressed in the blood vessels and trophoblast cells of the placenta. D3 catalyses inner ring deiodination of T4 to the biologically inactive reverse-triiodothyronine (rT3). Surprisingly, in the case of a fetus with a total thyroid hormone synthesis defect and evidence of circulating maternal thyroid hormone, the placenta does not have reduced D3 activity. This suggests to us that there may be other factors modulating T4 access to the deiodinase. Thyroid hormone (T4) is extremely hydrophobic and is carried in serum bound to three hepatically secreted thyroid hormone binding proteins, which are, in order of affinity for T4, thyroxine-binding globulin (TBG), TTR and albumin. We have recently described the synthesis of TTR, albumin and several other T4 binding proteins by human placenta. Earlier studies have shown that although TTR is present in high levels in fetal serum as early as 13 weeks gestation, very little mRNA can be detected in fetal liver at the same stage of development. We postulate that the TTR protein present in early fetal serum is of placental and/or maternal origin and its function is to deliver maternally derived T4 to the developing fetus and modulate interactions between D3 and T4.

We hypothesise that thyroid hormone (T4) is transferred, in a regulated manner, across the placenta from mother to fetus. This involves complex interplay/interactions between hormone transporters, deiodinating enzymes and thyroid hormone binding proteins. We also hypothesise that placental transthyretin (TTR) binds T4 and assists passage of thyroid hormone across the placenta, thereby avoiding deiodination by the abundant iodothyronine deiodinase type 3 (D3). TTR-T4 complex can then enter the fetal circulation.