Is a low level of free thyroxine in the maternal circulation associated with altered endothelial function in gestational diabetes?

Abstract

Synthesis of thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), in the human fetus starts from 17 to 19th weeks of gestation. Despite the majority of normal pregnant women reaching adequate levels of circulating thyroid hormones, in some cases, women with normal pregnancies have low level of free T4 during first trimester of pregnancy, suggesting that T4 action may be compromised in those women and their fetuses. In addition, pathological low levels of thyroid hormones are detected in isolated maternal hypothyroxemia (IMH) and clinical hypothyroidism. Nevertheless, human placenta regulates T3/T4 concentration in the fetal circulation by modulating the expression and activity of both thyroid hormone transporters (THT) and deiodinases. Then, placenta can control the availability of T3/T4 in the feto-placental circulation, and therefore may generate an adaptive response in cases where the mother courses with low levels of T4. In addition, T3/T4 might control vascular response in the placenta, in particularly endothelial cells may induce the synthesis and release of vasodilators such as nitric oxide (NO) or vasoconstrictors such as endothelin-1 mediated by these hormones. On the other hand, low levels of T4 have been associated with increase in gestational diabetes (GD) markers. Since GD is associated with impaired placental vascular function characterized by increased NO synthesis in placental arteries and veins, as well as elevated placental angiogenesis, it is unknown whether reduced T4 level at the maternal circulation could result in an altered placental endothelial function during GD. In this review, we analyze available information regarding thyroid hormones and endothelial dysfunction in GD; and propose that low maternal levels of T4 observed in GD may be compensated by increased placental availability of T3/T4 via elevation in the activity of THT and/or reduction in deiodinases in the feto-placental circulation.

Comparison of thyroid function tests and blood count in pregnant women with versus without gestational diabetes mellitus

“…Previous studies have indicated an association between the change in glucose metabolism and thyroid functions in patients with GDM. Presence of GDM was reported to be associated with low FT4 levels and high rates of isolated maternal hypothyroxinemia and subclinical hypothyroidism . Also, TSH levels were shown to be independently associated with poor glycemic control in GDM patients …”

“…Thyroid dysfunction is one of the most common endocrine gestational complications associated with adverse pregnancy outcomes . Notably, maternal thyroid hormone alterations, such as isolated maternal hypothyroxinemia and clinical hypothyroidism, have also been associated with GDM, while 4.3‐fold higher risk for developing GDM has been indicated among pregnant women in case of concomitant hypothyroidism …”

Free Thyroxine During Early Pregnancy and Risk for Gestational Diabetes

“…Recently, several studies among euthyroid women have reported associations between GDM and low free thyroxine (fT4) during the second and third trimesters [ 6 – 9 ] but not in the first trimester [ 7 , 9 , 10 ] offering a clue that thyroid hormones may provide further insight into pathogenesis. Guzman-Gutiérrez et al have recently proposed that the low level of fT4 associated with GDM may be compensated by increased placental availability of T3/T4 via elevation in the activity of thyroid hormone transporters and/or reduction in deiodinases in the feto-placental circulation [ 11 ].…”

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

“…However, there are no other studies that evaluate the neonatal thyroid profile from pregnancies with GDM. During pregnancy, T 4 and T 3 cross the placenta through Thyroid Hormone Transporters (THT), entering the placenta where they are regulated by deiodinases (DIO) [13,14]. DIO are seleno-enzymes responsible for the catabolism of specific iodine atoms of the iodothyronine molecule [15][16][17][18].…”