title: The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Clinical Biochemistry, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia.
authors.forename: Narelle C
authors.initials: NC
authors.lastname: Hadlow
authors.forename: Karen M
authors.initials: KM
authors.lastname: Rothacker
authors.forename: Robert
authors.initials: R
authors.lastname: Wardrop
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Ee Mun
authors.initials: EM
authors.lastname: Lim
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
mesh_terms: D000375:Aging / Q000097:blood*; D000465:Algorithms; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000097:blood; D007118:Immunoassay; D008297:Male; D008499:Medical Records; D008954:Models, Biological; D012016:Reference Values; D012189:Retrospective Studies; D012727:Sex Characteristics; D012995:Solubility; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood* / Q000737:chemistry; D015854:Up-Regulation; D014904:Western Australia
chemical_list: D013972:Thyrotropin; D013974:Thyroxine