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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

Walsh, John P., Ward, Lynley C., Burke, Valerie, Bhagat, Chotoo I., Shiels, Lauren, Henley, David, Gillett, Melissa J., Gilbert, Rhonda +2 more·2006·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2006-0099
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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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  • The evidence base to support titration of levothyroxine doses to achieve 'optimal' biochemical control of hypothyroidism is weak.

    “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]

  • Results of RCTs have indicated that cholesterol and SHBG levels are particularly affected by the administration of LT4.

    “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 a randomized controlled trial, patients were unable to detect differences in hypothyroid symptoms when LT4 dose was changed by approximately 20%, though the change was sufficient to modify cholesterol levels.

    “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]

  • 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.

    “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]

  • 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.

    “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]

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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.
ORCID
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
DOI
10.1210/jc.2006-0099
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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