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

Context: The relationship between TSH and T-4 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-T-4 relationship. Objective: The purpose of this study was to evaluate the TSH-free T-4 relationship in a large sample. Methods: 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 T-4 value (in picomoles per liter), the median TSH was calculated and analyzed by sex and age (in 20-year bands). Results: The relationship between log TSH and free T-4 was nonlinear. Mathematical modeling confirmed that it was described by 2 sigmoid curves with inflexion points at free T-4 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). Conclusions: The TSH-free T-4 relationship is not inverse log-linear but can be described by 2 overlapping negative sigmoid curves. At physiological free T-4 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 T-4 relationship, which is central to thyroid pathophysiology and laboratory diagnosis of thyroid disease.