Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects
Open accessAbstract
Background: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. Methods: A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. Results: At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 μg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Conclusions: Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.
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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 [36]
Altering LT4 dose over 6 months does not lead to significant changes in objective measures of quality of life, mood, or cognition.
“Altering the LT4 dose over 6 months does not lead to significant changes in the objective measures of quality of life, mood or cognition (75).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [75]
In these blinded studies, patients preferred higher perceived doses of levothyroxine, irrespective of the actual administered dose.
“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 [36]
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.
“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 [36]
In patients treated with LT4 who continue to report symptoms consistent with hypothyroidism, finely titrating TSH into specific tertiles of the expected range with small LT4 dose adjustments yields little or no benefit in validated measures of HR-QoL and cognition.
“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 [144]
Patients treated with LT4 were unable to correctly identify whether they had received the lower, medium, or higher dose.
“Most importantly, patients were unable to correctly identify whether they had received the lower, medium, or higher dose, but associated the higher dose with a perception of greater efficacy [144].”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [144]
Patients treated with LT4 associated the higher dose with a perception of greater efficacy.
“Most importantly, patients were unable to correctly identify whether they had received the lower, medium, or higher dose, but associated the higher dose with a perception of greater efficacy [144].”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [144]
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References 36 · Cited by 83
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- Authors
- Samuels, M. H., Kolobova, I., Niederhausen, M., Janowsky, J. S., & Schuff, K. G.
- Affiliations
- Oregon Health & Science University (US)
- Pennsylvania State University (US)
- Saturday Academy (US)
- Corresponding author
- Samuels, Mary H
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-03-02
- Volume
- 103
- Issue
- 5
- Pages
- 1997-2008
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC6457033
- OpenAlex
- W2793046691
- Cited by
- 83
- References
- 36
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 18 · 2021: 14 · 2020: 10 · 2019: 10 · 2018: 4
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR002369)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075496)
- National Center for Research Resources (K01RR024120)
- National Center for Advancing Translational Sciences
- 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
- levothyroxine, hypothyroidism, thyroid-stimulating hormone, quality of life, mood, cognition, executive function, memory
- MeSH terms
- Adult, Affect, Aged, Cognition, Dose-Response Relationship, Drug, Female, Humans, Hypothyroidism, Male, Middle Aged, Quality of Life, Thyrotropin, Thyroxine, Treatment Outcome, Hormone Replacement Therapy
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