Thyroid Function Characteristics and Determinants: The Rotterdam Study

Background: Information on determinants and change of thyroid function over time is sparse and conflicting but crucial for clinical interpretation and research. Therefore, our aim was to systematically investigate determinants of thyroid-stimulating hormone (TSH), free thyroxine (FT4) (as markers of thyroid function), their mutual relation (as marker of thyroid function set point) and changes in thyroid function over time. Methods: We included 9402 participants from the Rotterdam Study not taking thyroid medication and with available thyroid function measurements. Repeated measurements (6.5-year interval) were available for 1225 participants. The association of selected determinants with TSH, FT4, and their mutual relation (reflecting thyroid function set point) was estimated using linear regression models using restricted cubic splines with three knots. The factors investigated were age, sex, body mass index (BMI), tobacco smoking, alcohol use, thyroperoxidase antibodies (TPOAb), and common genetic factors. Results: Most influential determinants of TSH were age, smoking, genetic determinants, and TPOAb levels (p < 0.001). For FT4, most influential determinants were age, BMI, sex, genetic determinants and TPOAb levels (p < 0.001). Older age, female sex, and increased TPOAb levels were associated with a stronger relation between TSH and FT4. TSH levels did not change over time, irrespective of age. FT4 levels increased over time, most prominently in those older than 65 years of age (mean increase of 4.5 pmol/L). Conclusions: The main factors that influence the relationship between thyroid hormone and molar concentrations of TSH in our population-based cohort study are age, smoking, BMI, TPOAb levels, and common genetic variants. The set point that determines TSH secretion as it relates to negative thyroid hormone feedback is modified by age, sex and TPOAb positivity. FT4 levels increase over time, with a more pronounced increase in the elderly, while TSH values seem stable over time. Our results question the current notion of an increase of TSH with increasing age.