Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Estrada, Joshua M.; Soldin, Danielle; Buckey, Timothy M.; Burman, Kenneth D.; Soldin, Offie P.

doi:10.1089/thy.2013.0119

Cited by 64Thyroid Disorders and TreatmentsClinical Laboratory Practices and Quality ControlThyroid Cancer Diagnosis and Treatment

Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

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Estrada, Joshua M., Soldin, Danielle, Buckey, Timothy M., Burman, Kenneth D., Soldin, Offie P.·2014·Thyroid®

DOI 10.1089/thy.2013.0119PMC PMC3949435

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Abstract

Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis.

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The immunoreactivity of TSH may be affected by changes in glycosylation state such that immunoreactive TSH concentration may not reflect bioactivity at the thyroidal TSH receptor.
“As well as these analytical issues, as previously discussed, the immunoreactivity of TSH may be affected by changes in glycosylation state such that the immunoreactive TSH concentration may not reflect bioactivity at the thyroidal TSH receptor.122–124”
From Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status (2023) · cites this paper as [122]
While negative thyroid hormone feedback mitigates overproduction and hyperthyroidism, TRH is a potent defensive mechanism against undersupply, stimulating both pituitary TSH secretion and modulating its bioactivity.
“While negative thyroid hormone feedback mitigates thyroid hormone overproduction and hyperthyroidism, TRH is a potent defensive mechanism against undersupply, stimulating both pituitary TSH secretion and modulating its bioactivity (68–72).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [72]

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Background
IFCC international conventional reference procedure for the measurement of free thyroxine in serum: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group for Standardization of Thyroid Function Tests (WG-STFT) 1)
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Comparison of Pituitary and Recombinant Human Thyroid-stimulating Hormone (rhTSH) in a Multicenter Collaborative Study: Establishment of the First World Health Organization Reference Reagent for rhTSH
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Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex
Ehrenkranz, J., Bach, P. R., Snow, G. L., Schneider, A., Lee, J. L., Ilstrup, S., Bennett, S. T., & Benvenga, S. (2015) · Thyroid · doi:10.1089/thy.2014.0589 · Cited by 190 · see citing works
“The circadian variation in TSH is absent in infants younger than one month old (25) and in patients with Shee-han’s syndrome (26).”
Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00177 · Cited by 143 · see citing works
Laboratory Testing in Thyroid Conditions - Pitfalls and Clinical Utility
Soh, S.-B., & Aw, T.-C. (2019) · Annals of Laboratory Medicine · doi:10.3343/alm.2019.39.1.3 · Cited by 136 · see citing works
Thyroid function characteristics and determinants: the Rotterdam study.
Chaker, L., Korevaar, T. I. M., Medici, M., Uitterlinden, A. G., Hofman, A., Dehghan, A., Franco, O. H., & Peeters, R. P. (2016) · Thyroid · doi:10.1089/thy.2016.0133 · Cited by 118 · see citing works
“Lastly, another explanation for changes during aging is a change in TSH bioactivity (52), which was not measured in our study.”
Recent advances in central congenital hypothyroidism
Schoenmakers, N., Alatzoglou, K. S., Chatterjee, V. K., & Dattani, M. T. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0341 · Cited by 125 · see citing works
Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status
Van Uytfanghe, K., Ehrenkranz, J., Halsall, D., Hoff, K., Loh, T. P., Spencer, C. A., Köhrle, J., & ATA Thyroid Function Tests Writing Group (2023) · Thyroid® · doi:10.1089/thy.2023.0169 · Cited by 100 · see citing works
Thyroid function across the lifespan: do age-related changes matter?
Walsh, J. P. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2022.1463 · Cited by 59 · see citing works
“Notably, circulating TSH exists in several different isoforms with varying degrees of glycosylation, sialylation, and sulfonation which affect tissue availability and bioactivity [10,11]; this is not reflected in immunoreactive TSH concentrations determined by routine laboratory assays.”
Background
Reporting Thyroid Function Tests in Pregnancy.
McNeil, A. R., & Stanford, P. E. (2015) · Europe PMC (PubMed Central) · Cited by 56 · see citing works
Reference interval of thyroid stimulating hormone and free thyroxine in a reference population over 60 years old and in very old subjects (over 80 years): comparison to young subjects
Fontes, R. G., Coeli, C. M., AGUIAR, F. P. L., & Vaisman, M. (2013) · Thyroid Research · doi:10.1186/1756-6614-6-13 · Cited by 47 · see citing works
Free thyroxine measurement in clinical practice: how to optimize indications, analytical procedures, and interpretation criteria while waiting for global standardization
D’Aurizio, F., Kratzsch, J., Gruson, D., Ovčariček, P. P., & Giovanella, L. (2022) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2022.2121960 · Cited by 31 · see citing works
Cardiovascular Risk and Quality of Life in Elderly People with Mild Thyroid Hormone Deficiency
Tognini, S., Pasqualetti, G., Calsolaro, V., Polini, A., Caraccio, N., & Monzani, F. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00153 · Cited by 23 · see citing works
Thyroid stimulating hormone (TSH) autoregulation reduces variation in the TSH response to thyroid hormones
Fitzgerald, S. P., & Bean, N. G. (2018) · Temperature · doi:10.1080/23328940.2018.1513110 · Cited by 21 · see citing works
“[25] Estrada JM, Soldin D, Buckey TM, et al.”
Background
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“Elevated TSH level which is not on line with T3 and T4 levels together with hCS could be indicative of reduced bioactivity of TSH (22, 25, 41).”
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The association between serum TSH concentration whithin the normal range and nutritional status in euthyroid pregnant women at the first trimester of gestation
Mardanian, F., Goodarzi-Khoigani, M., Mahmoodabad, S. S. M., Moghadam, M. H. B., Nadjarzadeh, A., Feizi, A., Allameh, Z. S., & Molavi, S. (2021) · Journal of Research in Medical Sciences · doi:10.4103/jrms.jrms_780_20 · Cited by 9 · see citing works
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The interference of anti-TSH autoantibody on clinical TSH detection
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“Our data, however, indicate that at least one of the Abbott or Roche TSH assays is not ‘blind’ to the pituitary TSH isoforms when compared to circulating TSH.”
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Authors: Estrada, J. M., Soldin, D., Buckey, T. M., Burman, K. D., & Soldin, O. P.
Affiliations: Georgetown University Medical Center (US)
MedStar Washington Hospital Center (US)
Corresponding author: Soldin, Offie P.
ORCID: Buckey, Timothy M.
Burman, Kenneth D.
Soldin, Offie P.
Venue: Thyroid®
Publisher: SAGE Publications
Published: 2014-03
Volume: 24
Issue: 3
Pages: 411-423
ISSN: 1050-7256 (ISSN-L)
1557-9077
DOI: 10.1089/thy.2013.0119
PMC: PMC3949435
OpenAlex: W2178118369
Cited by: 64
References: 151
Citations by year: 2026: 1 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 1
FWCI: 0.59
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Thyroid (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Aging (NIHR01AG033867)
National Cancer Institute (P30CA051008)
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, TSH immunoassay, primary hypothyroidism, thyroid function tests, free triiodothyronine, free thyroxine, TSH receptor
MeSH terms: Humans, Hypothyroidism, Immunoassay, Thyroid Function Tests, Thyrotropin, Protein Isoforms

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Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

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