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Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial
Abstract
BACKGROUND: Levothyroxine sodium is widely prescribed to treat primary hypothyroidism. There is consensus that levothyroxine should be taken in the morning on an empty stomach. A pilot study showed that levothyroxine intake at bedtime significantly decreased thyrotropin levels and increased free thyroxine and total triiodothyronine levels. To date, no large randomized trial investigating the best time of levothyroxine intake, including quality-of-life evaluation, has been performed. METHODS: To ascertain if levothyroxine intake at bedtime instead of in the morning improves thyroid hormone levels, a randomized double-blind crossover trial was performed between April 1, 2007, and November 30, 2008, among 105 consecutive patients with primary hypothyroidism at Maasstad Hospital Rotterdam in the Netherlands. Patients were instructed during 6 months to take 1 capsule in the morning and 1 capsule at bedtime (one containing levothyroxine and the other a placebo), with a switch after 3 months. Primary outcome measures were thyroid hormone levels; secondary outcome measures were creatinine and lipid levels, body mass index, heart rate, and quality of life. RESULTS: Ninety patients completed the trial and were available for analysis. Compared with morning intake, direct treatment effects when levothyroxine was taken at bedtime were a decrease in thyrotropin level of 1.25 mIU/L (95% confidence interval [CI], 0.60-1.89 mIU/L; P < .001), an increase in free thyroxine level of 0.07 ng/dL (0.02-0.13 ng/dL; P = .01), and an increase in total triiodothyronine level of 6.5 ng/dL (0.9-12.1 ng/dL; P = .02) (to convert thyrotropin level to micrograms per liter, multiply by 1.0; free thyroxine level to picomoles per liter, multiply by 12.871; and total triiodothyronine level to nanomoles per liter, multiply by 0.0154). Secondary outcomes, including quality-of-life questionnaires (36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale, 20-Item Multidimensional Fatigue Inventory, and a symptoms questionnaire), showed no significant changes between morning vs bedtime intake of levothyroxine. CONCLUSIONS: Levothyroxine taken at bedtime significantly improved thyroid hormone levels. Quality-of-life variables and plasma lipid levels showed no significant changes with bedtime vs morning intake. Clinicians should consider prescribing levothyroxine intake at bedtime. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN17436693 (NTR959).
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“TSH values were 0.9-1.6 mIU/L higher with the morning compared with the bedtime LT4 ingestion (129).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [129]
In the citing paper
“Two recent cross-over studies had different findings with the lowest serum TSH values being seen either 1 hour before breakfast or at bedtime (128,129).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [129]
In the citing paper
“Four studies (121,126,128,129), out of the six studies examining this issue (121,128-131), have shown that the timing of LT4 administration influences the serum TSH values of hypothyroid patients receiving treatment.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [129]
In the citing paper
“In 2010, a randomized, double-blind, crossover trial recruiting 90 patients examined the efficacy of taking LT4 at bedtime (104). Reduced TSH levels and elevated total T3 and total T4 (TT4) levels were observed in patients taking LT4 at bedtime, with no significant difference in quality of life or preference.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [104]
In the citing paper
“Bolk et al. reported that administration of LT4 at bedtime was associated with higher thyroid hormone concentrations and lower TSH concentrations than administration in the morning [ 35 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [35]
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Metadata
- Authors
- Bolk, N.
- Affiliations
- Maasstad Ziekenhuis (NL)
- Corresponding author
- Bolk, Nienke
- Venue
- Archives of Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2010-12-13
- Volume
- 170
- Issue
- 22
- Pages
- 1996
- ISSN
- 0003-9926 (ISSN-L)
- OpenAlex
- W2167956101
- Cited by
- 128
- References
- 38
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 12 · 2020: 10 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 10 · 2015: 10 · 2014: 10 · 2013: 12 · 2012: 9
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (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 › Adrenal Hormones and Disorders
- Keywords
- bedtime dosing, morning dosing, primary hypothyroidism, thyroid-stimulating hormone, free thyroxine, triiodothyronine, thyroid hormone levels, quality of life, fatigue, serum lipids, creatinine, heart rate, body mass index, crossover trial, medication adherence
- MeSH terms
- Adult, Aged, Creatinine, Double-Blind Method, Drug Administration Schedule, Female, Heart Rate, Humans, Hypothyroidism, Lipids, Male, Middle Aged, Netherlands, Quality of Life, Surveys and Questionnaires, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine, Body Mass Index, Cross-Over Studies, Hormone Replacement Therapy
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