Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels
Abstract
CONTEXT: TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated. OBJECTIVE: With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity. SETTING: The study was performed at a university hospital. DESIGN AND SUBJECTS: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis. RESULTS: Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH. CONCLUSIONS: FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.
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Whereas serum free T4 remains constant over 24 h, there is a circadian free T3 rhythm with its acrophase occurring around 3 a.m., approximately 90 min after TSH acrophase.
“Whereas serum free T4 remains constant over 24 h, there is a circadian free T3 rhythm with its acrophase occurring around 3 a.m., approximately 90 min after TSH acrophase [77] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [77]
T3 remains stable with a <10% variance throughout the day in healthy individuals.
“Considering the fact that T3 remains stable with a <10% variance throughout the day in healthy individuals (167), it is no wonder that patients receiving T3 monotherapy or combined therapy present with increasing hyperthyroid symptoms (eg, palpitations, irritability, tremor, and shortness of breath) (168).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [167]
A direct TSH-deiodinase link may at least partly explain the T3 circadian rhythm accompanying that of TSH, while FT4 shows no such related circadian or seasonal rhythm.
“A direct TSH-deiodinase link may, at least partly, explain the T3 circadian rhythm accompanying that of TSH, while FT4 shows no such related circadian or seasonal rhythm (137–139).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [138]
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References 25 · Cited by 219
- Authors
- Russell, W., Harrison, R. F., Smith, N., Darzy, K., Shalet, S., Weetman, A. P., & Ross, R. J.
- Affiliations
- University of Sheffield (GB)
- Royal Hallamshire Hospital (GB)
- The Christie Hospital (GB)
- Corresponding author
- Ross, R. J.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-06-01
- Volume
- 93
- Issue
- 6
- Pages
- 2300-2306
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2063068406
- Cited by
- 219
- References
- 25
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 20 · 2023: 12 · 2022: 20 · 2021: 11 · 2020: 13 · 2019: 11 · 2018: 15 · 2017: 16 · 2016: 13 · 2015: 13 · 2014: 13 · 2013: 11 · 2012: 10
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- free triiodothyronine, free thyroxine, thyroid-stimulating hormone, circadian rhythm, thyroid hormone replacement, thyroid hormone synthesis, cosinor analysis
- MeSH terms
- Adolescent, Adult, Analysis of Variance, Circadian Rhythm, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Pulsatile Flow, Thyrotropin, Thyroxine, Time Factors, Triiodothyronine, Models, Statistical
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