Early Life Impacts of Thyroid Function and Human Chorionic Gonadotropin

This thesis investigates developmental and metabolic aspects of hormonal influence in early life. The focus was on pregnancy as well as on early childhood. The associations of Human Chorionic Gonadotropin (hCG) and thyroid function with pregnancy outcomes were examined and we aimed to investigate potential underlying mediating pathways and delineate the effects of thyroid hormone and hCG. We investigated the functionality of hypothalamic-pituitary-thyroid axis and determinants of thyroid function at early childhood. The effects of childhood thyroid function on major target organ such as the cardiovascular system and bone were investigated.
Chapter 1 provides the background on the physiology of pregnancy and childhood and the endocrinological aspects relevant for both pregnant women and the offspring. The aims of this thesis are described and the setting of the studies is presented.
Chapter 2 focuses on the effects of thyroid function in pregnancy in terms of the placental function and metabolism of homocysteine. In Chapter 2.1, we show that high thyroid hormone in early pregnancy is associated with high placental vascular resistance in the second and third trimester, in both maternal and fetal placental compartment. Our results also suggest that these effects might have a limited mediating role in the effects of thyroid function on pre-eclampsia and birth weight. Chapter 2.2 describes the association of thyroid function with homocysteine concentrations in pregnant women and in neonates. High thyroid hormone was associated with high homocysteine concentrations and the results suggest that the depleting effects of thyroid hormone on folate and vitamin B12 may have a role in this association.
Chapter 3 investigates the associations of hCG concentrations with fetal growth patterns and the risk of pre-eclampsia. Chapter 3.1 shows an association of high total hCG with a high risk of pre-eclampsia, which could be partially explained by the effects of hCG on the balance between pro- and anti-angiogenic factors, PlGF and sFlt-1. Chapter 3.2 unravels the pattern of the association of hCG with fetal growth and shows that association of low total hCG in the late first trimester with low birth weight arises due to a decrease in fetal growth in these pregnancies. In both Chapter 3.1 and 3.2, sex-specific differences in the associations of hCG with the outcomes of interest were detected.
Chapter 4 focuses on the aspects of thyroid function in childhood and investigates major determinants of childhood TSH and FT4 concentration, as well as variability in the existing pediatric reference ranges and the effects of thyroid function on major target organs. Chapter 4.1 provides a literature overview of published reference ranges for thyroid function in children, showing differences across age categories, assay use and population size. Child age, sex, ethnicity and anthropometric characteristics were identified as major thyroid function determinants and a stable association of FT4 and TSH is shown. Chapter 4.2 shows that thyroid function is a determinant of left ventricular mass and this was partially mediated by the effects of FT4 on the lean body mass. TSH and FT4 were positively associated with blood pressure, with a potential role of arterial stiffness in the latter case, suggesting different mechanisms via which these two hormones are associated with blood pressure. In Chapter 4.3, we show a consistent inverse association of FT4 with bone density and show an association of TSH with bone density which was not consistent among the European subgroup.
In Chapter 5, an interpretation of the main findings of this thesis is provided and methodological considerations, clinical implications of the detected associations, as well as future perspectives for the field are discussed.