Circulating Thyroid Hormone Concentrations and Placental Thyroid Hormone Receptor Expression in Normal Human Pregnancy and Pregnancy Complicated by Intrauterine Growth Restriction (IUGR)

Abstract

Thyroid hormones are critical to growth and development of the human fetus. Abnormal placental development, a major cause of intrauterine growth restriction (IUGR), is associated with a high perinatal mortality and morbidity. Thyroid status has been postulated to play a role in the pathogenesis of such morbidity. In the present study, we have investigated fetal thyroid function and placental expression of thyroid hormone receptor (TR) alpha and beta variants during normal human pregnancy and in pregnancy associated with IUGR. Measurement of free thyroid hormones and TSH concentrations revealed significant rises in free T4 and free T3 between the second and third trimesters of normal pregnancy. Serum concentrations of free T4 and free T3 were lower in fetuses affected by IUGR, although serum TSH levels were not significantly different. Immunocytochemistry demonstrated the presence of TR alpha1, alpha2, and beta1 proteins within the nuclei of trophoblast and stromal placental cells. Immunostaining for these TR variants increased with increasing gestation in normal placenta. Comparison of IUGR placental samples with normal samples revealed greater immunostaining for TR alpha1, alpha2, and beta1 variants in IUGR. Examination of pretranslational expression of TR alpha1, alpha2, beta1, and beta2 variants by semiquantitative RT-PCR revealed increasing expression of TR alpha1, alpha2, and beta2 messenger RNAs with increasing gestation in normal pregnancy, which "mirrored" post-translational expression. However, and in contrast, there were no significant differences in expression of TR messenger RNAs in normal and IUGR placenta. The present findings of reduction in serum free thyroid hormones and increased expression of TR alpha and beta proteins in association with IUGR highlight the potential importance of thyroid status in influencing long-term fetal outcome in this condition.

Management of subclinical hypothyroidism in pregnancy: are we too simplistic?

“…The low levels of foetal THs in early pregnancy, confirmed by others, support the discussed high efficacy of placental regulation to optimise circulating TH levels for the foetal demands during the respective stage of pregnancy whilst allowing local activation of THs to satisfy independent spatial and temporal requirements of each tissue depending on the developmental stage (54). The continued transfer of THs from mother to foetus until delivery is exemplified in studies of athyreotic neonates at birth, which demonstrate that maternal TH transfer occurs and can enable them to reach TH concentrations of w50% of a normal neonate (71).…”

“…(54). Tri-iodothyronine (T 3 ) is able to alter the cytokine network in a cell-type and gestational agedependent manner in human utero-placental cells (55) and promote human trophoblast invasion (56).…”

Thyroid hormones in fetal growth and prepartum maturation

“…Thyroid hormone concentrations are low in IUGR and small-for-gestational-age fetuses both in human populations and when fetal growth is restricted in experimental animals by undernutrition and placental insufficiency (Wrutniak & Cabello 1983, Thorpe-Beeston et al 1991b, Kilby et al 1998, Rae et al 2002, Pereira & Procianoy 2003. In several of the experimental studies, plasma T 4 concentrations are correlated positively to the body weight of the fetal and/or newborn animals (Wrutniak & Cabello 1983, Fowden & Silver 1995.…”

The role of the placenta in thyroid hormone delivery to the fetus

“…53 Thyroid hormone receptors are ubiquitously expressed in uteroplacental tissues from the first trimester of pregnancy, and their expression increases with gestational age. 8,54 Saturation of endogenous nuclear T 3 -binding sites has been estimated to be only 34% in term placental and decidual homogenates, 55 which is unlikely to be sufficient to significantly influence maternal-fetal transfer of thyroid hormones.…”