The Relationship Between TSH and Free T4 in a Large Population Is Complex and Nonlinear and Differs by Age and Sex

The relationship between TSH and T4 is thought to be inverse log-linear, but recent studies have challenged this. There are limited data regarding age and sex differences in the TSH-T4 relationship. The purpose of this study was to evaluate the TSH–free T4 relationship in a large sample. In a cross-sectional, retrospective study, we analyzed TSH and free T4 results from 152 261 subjects collected over 12 years by a single laboratory. For each free T4 value (in picomoles per liter), the median TSH was calculated and analyzed by sex and age (in 20-year bands). The relationship between log TSH and free T4 was nonlinear. Mathematical modeling confirmed that it was described by 2 sigmoid curves with inflexion points at free T4 concentrations of 7 and 21 pmol/L. For free T4 within the reference range (10–20 pmol/L), median TSH was higher in men than in women (P < .001) and increased across age bands with the highest values in those 80 years and older (P < .001). In contrast, in overt hypothyroidism (n = 4403), TSH was lower in older age groups than in those aged 20–39 years (P < .001). The TSH–free T4 relationship is not inverse log-linear but can be described by 2 overlapping negative sigmoid curves. At physiological free T4 concentrations, TSH is higher in men and in older people, whereas the TSH response to hypothyroidism is more robust in younger people. These results advance understanding of the TSH–free T4 relationship, which is central to thyroid pathophysiology and laboratory diagnosis of thyroid disease.