The DOI matches its Crossref record; 29 of the 31 references it cites were found in a registry or an index.
Small Changes in Thyroxine Dosage Do Not Produce Measurable Changes in Hypothyroid Symptoms, Well-Being, or Quality of Life: Results of a Double-Blind, Randomized Clinical Trial
Abstract
Context: In patients with primary hypothyroidism, anecdotal evidence suggests that well-being is optimized by fine adjustment of T4 dosage, aiming for a serum TSH concentration in the lower reference range. This has not been tested in a clinical trial. Objective: Our objective was to test whether adjustment of T4 dosage aiming for a serum TSH concentration less than 2 mU/liter improves well-being compared with a serum TSH concentration in the upper reference range. Design: We conducted a double-blind, randomized clinical trial with a crossover design. Participants: Fifty-six subjects (52 females) with primary hypothyroidism taking T4 (≥100 μg/d) with baseline serum TSH 0.1–4.8 mU/liter participated. Interventions: Each subject received three T4 doses (low, middle, and high in 25-μg increments) in random order. Outcome Measures: Outcome measures included visual analog scales assessing well-being (the primary endpoint) and hypothyroid symptoms, quality of life instruments (General Health Questionnaire 28, Short Form 36, and Thyroid Symptom Questionnaire), cognitive function tests, and treatment preference. Results: Mean (± sem) serum TSH concentrations were 2.8 ± 0.4, 1.0 ± 0.2, and 0.3 ± 0.1 mU/liter for the three treatments. There were no significant treatment effects on any of the instruments assessing well-being, symptoms, quality of life, or cognitive function and no significant treatment preference. Conclusions: Small changes in T4 dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life, despite the expected changes in serum TSH and markers of thyroid hormone action. These data do not support the suggestion that the target TSH range for the treatment of primary hypothyroidism should differ from the general laboratory range.
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In the citing paper
“the evidence base to support titration of levothyroxine doses to achieve ' optimal ' biochemical control of hypothyroidism is weak, 35,36”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [35]
In the citing paper
“The results of RCTs have indicated that cholesterol (50,82-86), and SHBG levels (50) are particularly affected by the administration of LT4.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [50]
In the citing paper
“A randomized controlled trial (RCT) demonstrated that patients are unable to detect differences in the symptoms associated with hypothyroidism when the LT4 dose is changed by approximately 20%. Of note, the change in dosage was sufficient to modify cholesterol levels (50).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [50]
In the citing paper
“Moreover, a randomized cross-over study of 8 weeks' duration did not show changes in well-being or quality of life with TSH titration within the normal and subnormal range (50).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [50]
In the citing paper
“This broad range might explain why there is no benefit from targeting low-normal versus high-normal TSH concentrations when patients are analysed as a group, but individual patients might benefit.166”
From Hypothyroidism (2024) · cites this paper as [166]
In the citing paper
“However, in these blinded studies patients preferred higher perceived doses of levothyroxine, irrespective of the actual administered dose.”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [35]
In the citing paper
“Two studies which blinded patients to the strength of their levothyroxine replacement and performed detailed symptom and QoL analysis showed that patients cannot tell what dose of levothyroxine they are taking. 35,36”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [35]
In the citing paper
“These small changes in L-T4 dosage did not produce measurable changes in hypothyroid symptoms, well-being, quality of life, or cognition, and no significant treatment preference was observed.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [29]
In the citing paper
“Two excellent prospective controlled studies have used validated measures of health-related quality of life (HR-QoL) and cognition to demonstrate little or no benefit from this approach [143, 144].”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [143]
Citations
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A scaled version of the General Health Questionnaire
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Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism
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The Evidence for a Narrower Thyrotropin Reference Range Is Compelling
Wartofsky, L., & Dickey, R. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0455 · Cited by 424
L-Thyroxine Therapy in Subclinical Hypothyroidism: A Double-Blind, Placebo-Controlled Trial
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Flagged first, then by citations
2 of the 31 references couldn’t be matched to a known paper.
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Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., et al. (2014) · Thyroid® · doi:10.1089/thy.2014.0028 · Cited by 1,928
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567
Chaker, L., Bianco, A. C., Jonklaas, J., & Peeters, R. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30703-1 · Cited by 1,159
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053
Subclinical Hypothyroidism: A Review
Biondi, B., Cappola, A. R., & Cooper, D. S. (2019) · JAMA · doi:10.1001/jama.2019.9052 · Cited by 604
Metadata
- Authors
- Walsh, J. P., Ward, L. C., Burke, V., Bhagat, C. I., Shiels, L., Henley, D., Gillett, M. J., Gilbert, R., Tanner, M., & Stuckey, B. G. A.
- Affiliations
- The University of Western Australia (AU)
- Departments of Endocrinology and Diabetes (J.P.W., L.C.W., B.G.A.S., D.H., M.J.G.) Nedlands, Western Australia 6009
- Pathwest Laboratory Medicine (AU)
- Psychiatry and Behavioural Science (L.S.), Nedlands, Western Australia 6009
- Corresponding author
- Walsh, John P.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2006-07-01
- Volume
- 91
- Issue
- 7
- Pages
- 2624-2630
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2085495215
- Cited by
- 164
- References
- 31
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 15 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 8 · 2017: 11 · 2016: 9 · 2015: 4 · 2014: 9 · 2013: 12 · 2012: 8
- FWCI
- 4.88
- 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 › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- primary hypothyroidism, levothyroxine dosage, serum TSH, well-being, quality of life, cognitive function, treatment preferences, thyroid hormone replacement
- MeSH terms
- Adult, Cognition, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hypothyroidism, Male, Middle Aged, Quality of Life, Surveys and Questionnaires, Thyrotropin, Thyroxine, Triiodothyronine, Treatment Outcome
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