The Relationship Between TSH and Free T4 in a Large Population Is Complex and Nonlinear and Differs by Age and Sex
Abstract
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.
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TSH is the preferred marker of thyroid status.
“TSH is the preferred marker of thyroid status. 5”
From Hypothyroidism (2024) · cites this paper as [5]
The Materials and Methods describe TSH as a thyroid function test, and the Discussion uses TSH levels in defining hypothyroidism. These passages support its use as a marker of thyroid status, but our copy does not say it is the preferred marker over other tests. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe TSH-FT4 relationship differs with age, with older people having higher TSH concentrations at any given FT4 level than younger individuals.
“In a large laboratory database study, 5 the TSH-FT4 relationship differs with age, with older people having higher TSH concentrations at any given FT4 level than younger individuals.”
From Hypothyroidism (2024) · cites this paper as [5]
The Discussion and ‘Age effects in untreated subjects’ report higher TSH in older people at the same free T4 concentration within the reference range (10–20 pmol/L). But ‘Age and TSH in untreated hypothyroidism’ reports lower TSH in older groups after adjustment for free T4. The claim’s ‘at any given FT4 level’ therefore extends the finding beyond the range where it holds. (LLM, conf=0.91)
Experimental — accuracy not yet measuredThe hypothalamic pituitary thyroid axis is altered with age and older individuals have been shown to exhibit a blunted TSH response to thyroid hormone deficiency.
“The hypothalamic pituitary thyroid axis is altered with age and older individuals have been shown to exhibit a blunted TSH response to thyroid hormone deficiency [4, 23].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [4]
The relationship between TSH and T4 varies amongst individuals and is affected by age, smoking, levothyroxine treatment, and the presence of antibodies.
“Furthermore, the relationship between TSH and T4 varies amongst individuals and is affected, amongst other factors, by age, smoking, levothyroxine treatment, and the presence of antibodies [12, 15, 16].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [12]
The relationship between TSH and T4 approximates to an inverse log-linear relationship for most individuals, and this relationship becomes clearer for a given individual when more data points are available to define it.
“The precise nature of the relationship remains under debate, but the relationship between TSH and T4 approximates to an inverse log-linear relationship for most individuals, and this relationship becomes clearer for a given individual when more data points are available to define it [12–14].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [12]
The TSH-FT4 relationship is not proportional and log-linear; it is curvilinear and damped in the middle euthyroid part, with steeper gradients at the hypothyroid or hyperthyroid extremes.
“Large cross-sectional studies have examined the TSH–FT4 relationship over the entire functional range but did not confirm a proportional and log-linear TSH–FT4 relationship, rather suggesting that the TSH response to changes in FT4 is curvilinear and damped in the middle part (6, 7, 9, 33) (Figure 2).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [7]
The non-linearity of the logTSH-FT4 relationship has been independently confirmed by several groups and replicated in a prospective study involving 1912 subjects.
“The non-linearity of the logTSH–FT4 relationship has been independently confirmed by several groups and was replicated in a prospective study involving 1912 subjects (7–9, 33, 34).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [7]
The molecular mechanisms defining multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation may explain the disproportional non-logarithmic behavior of the TSH-FT4 relationship.
“Taken together, the molecular mechanisms defining multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation may explain the disproportional non-logarithmic behavior of the TSH–FT4 relationship (Figure 2) (6–9, 33, 34).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [7]
The TSH-T4 relationship is not inverse log-linear but consists of two overlapping negative sigmoid curves and varies with age and sex.
“This is not an inverse log-linear relationship but is composed of two overlapping negative sigmoid curves, and it varies with age and sex.28”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [28]
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- Authors
- Hadlow, N. C., Rothacker, K. M., Wardrop, R., Brown, S. J., Lim, E. M., & Walsh, J. P.
- Affiliations
- The University of Western Australia (AU)
- Sir Charles Gairdner Hospital (AU)
- Queen Elizabeth II Medical Centre (AU)
- Corresponding author
- Walsh, John P.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2013-07-01
- Volume
- 98
- Issue
- 7
- Pages
- 2936-2943
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2047159776
- Cited by
- 203
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 10 · 2023: 33 · 2022: 14 · 2021: 15 · 2020: 25 · 2019: 14 · 2018: 14 · 2017: 17 · 2016: 15 · 2015: 7 · 2014: 8 · 2013: 3
- FWCI
- 8.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid-stimulating hormone, free thyroxine, age differences, sex differences, overt hypothyroidism, thyroid function, thyroid pathophysiology
- MeSH terms
- Aging, Algorithms, Cross-Sectional Studies, Female, Humans, Hypothyroidism, Immunoassay, Male, Medical Records, Models, Biological, Reference Values, Retrospective Studies, Sex Characteristics, Solubility, Thyrotropin, Thyroxine, Western Australia, Cohort Studies, Down-Regulation, Up-Regulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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