The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex

J Clin Endocrinol Metab. 2013 Jul;98(7):2936-43. doi: 10.1210/jc.2012-4223. Epub 2013 May 13.


Context: 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.

Objective: The purpose of this study was to evaluate the TSH-free T₄ 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 T₄ 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 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).

Conclusions: 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.

MeSH terms

  • Aging / blood*
  • Algorithms
  • Cohort Studies
  • Cross-Sectional Studies
  • Down-Regulation
  • Female
  • Humans
  • Hypothyroidism / blood
  • Immunoassay
  • Male
  • Medical Records
  • Models, Biological*
  • Reference Values
  • Retrospective Studies
  • Sex Characteristics
  • Solubility
  • Thyrotropin / blood*
  • Thyroxine / blood*
  • Thyroxine / chemistry
  • Up-Regulation*
  • Western Australia


  • Thyrotropin
  • Thyroxine