Evaluation of bedtime vs morning levothyroxine intake to control hypothyroidism in older patients: a pragmatic crossover randomized clinical trial
Open accessAbstract
Introduction Drug scheduling in older adults can be a challenge, especially considering polypharmacy, physical dependency, and possible drug interactions. Properly testing alternative treatment regimens could therefore help to overcome treatment barriers. Hypothyroidism is a prevalent condition in older adults, however, studies evaluating L-thyroxine treatment effectiveness in this specific age group are still lacking. Most studies testing an evening administration of levothyroxine were mainly composed of younger adults. Therefore, this trial is aimed to assess if evening levothyroxine (LT4) administration can effectively control hypothyroidism in older patients. Materials and Methods A randomized crossover clinical trial was conducted between June 2018 and March 2020 at the Hospital de Clínicas de Porto Alegre, a teaching hospital in Brazil, to compare the efficacy of morning and evening administration of LT4 for hypothyroidism control in older patients. The study protocol is published elsewhere. A total of 201 participants, ≥60 years old, with primary hypothyroidism treated with LT4 for at least 6 months and on stable doses for at least 3 months were included. Participants were randomly assigned to a starting group of morning LT4 intake (60 min before breakfast) or bedtime LT4 intake (60 min after the last meal). After ≥12 weeks of follow-up, a crossover between strategies was performed. The primary outcome was the change in serum thyrotropin (Thyroid-Stimulating Hormone; TSH) levels after 12 weeks of each LT4 administration regimen. Results A total of 201 participants with mean age of 72.4 ± 7.2 years were included, out of which 84.1% were women; baseline characteristics and frequency of controlled hypothyroidism were similar between groups. Mean baseline TSH was 3.43 ± 0.25 mUI/L. In total, 118 participants attended three meetings, allowing 135 comparisons by crossover analytic strategy. Mean TSH levels after follow-up were 2.95 ± 2.86 in the morning group and 3.64 ± 2.86 in the bedtime group,p= 0.107. Discussion Thyroid-Stimulating Hormone levels and frequency of controlled hypothyroidism were similar during the follow-up period regardless of the treatment regimen (morning or bedtime).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A randomized crossover trial in 201 older patients (60 years or older) did not detect any significant differences in mean TSH levels between an hour before breakfast administration versus an hour after evening meal dosing regimen.
“A randomized crossover trial in 201 older patients (60 years or older) did not detect any significant differences in the mean TSH levels between an hour before breakfast administration versus an hour after evening meal dosing regimen (43).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [43]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Hollowell, J. G., Staehling, N. W., Flanders, W. D., Hannon, W. H., Gunter, E. W., Spencer, C. A., & Braverman, L. E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.2.489 · Cited by 4,279 · see citing works
The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey
Vanderpump, M. P. J., Tunbrldge, W. M. G., French, J. M., Appleton, D., Bates, D., Clark, F., Evans, J. G., Hasan, D. M., Rodgers, H., Tunbridge, F., et al. (1995) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1995.tb01894.x · Cited by 2,432 · see citing works
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 · see citing works
Global epidemiology of hyperthyroidism and hypothyroidism
Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.18 · Cited by 1,552 · see citing works
Williams Textbook of Endocrinology
Reutrakul, S. (2009) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000323673.44568.e8 · Cited by 710 · see citing works
An update on the clinical consequences of polypharmacy in older adults: a narrative review
Wastesson, J. W., Morin, L., Tan, E. C. K., & Johnell, K. (2018) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2018.1546841 · Cited by 617 · see citing works
Comparison of drug adherence rates among patients with seven different medical conditions
Briesacher, B. A., Andrade, S. E., Fouayzi, H., & Chan, K. A. (2008) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.28.4.437 · Cited by 587 · see citing works
Timing of levothyroxine administration affects serum thyrotropin concentration
Bach-Huynh, T.-G., Nayak, B., Loh, J., Soldin, S., & Jonklaas, J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0860 · Cited by 198 · see citing works
Gastrointestinal malabsorption of thyroxine
Virili, C., Antonelli, A., Santaguida, M. G., Benvenga, S., & Centanni, M. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00168 · Cited by 164 · see citing works
Delayed Intestinal Absorption of Levothyroxine
BENVENGA, S., BARTOLONE, L., SQUADRITO, S., GIUDICE, F. L., & TRIMARCHI, F. (1995) · Thyroid · doi:10.1089/thy.1995.5.249 · Cited by 156 · see citing works
Aspects of the absorption of oral L-thyroxine in normal man
Wenzel, K. W., & Kirschsieper, H. E. (1977) · Metabolism · doi:10.1016/0026-0495(77)90121-4 · Cited by 151 · see citing works
Localization of human thyroxine absorption
HAYS, M. T. (1991) · Thyroid · doi:10.1089/thy.1991.1.241 · Cited by 138 · see citing works
Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial
Bolk, N. (2010) · Archives of Internal Medicine · doi:10.1001/archinternmed.2010.436 · Cited by 128 · see citing works
Sachmechi, I., Reich, D. M., Aninyei, M., Wibowo, F., Gupta, G., & Kim, P. J. (2007) · Endocrine Practice · doi:10.4158/ep.13.4.345 · Cited by 112 · see citing works
Bolk, N., Visser, T. J., Kalsbeek, A., van Domburg, R. T., & Berghout, A. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02681.x · Cited by 96 · see citing works
Absorption of Levothyroxine When Coadministered with Various Calcium Formulations
Zamfirescu, I., & Carlson, H. E. (2011) · Thyroid · doi:10.1089/thy.2010.0296 · Cited by 76 · see citing works
A. Irving, S., Vadiveloo, T., & Leese, G. P. (2015) · Clinical Endocrinology · doi:10.1111/cen.12559 · Cited by 69 · see citing works
Human Thyroxine Absorption: Age Effects and Methodological Analyses
HAYS, M. T., & NIELSEN, K. R. K. (1994) · Thyroid · doi:10.1089/thy.1994.4.55 · Cited by 67 · see citing works
Thyroxine and treatment of hypothyroidism: seven decades of experience
Mateo, R. C. I., & Hennessey, J. V. (2019) · Endocrine · doi:10.1007/s12020-019-02006-8 · Cited by 57 · see citing works
Rajput, R., Chatterjee, S., & Rajput, M. (2011) · Journal of Thyroid Research · doi:10.4061/2011/505239 · Cited by 52 · see citing works
Levothyroxine absorption in health and disease, and new therapeutic perspectives.
Ianiro, G., Mangiola, F., Rienzo, T. A. D., Bibbò, S., Franceschi, F., Greco, A. V., & Gasbarrini, A. (2014) · PubMed · Cited by 51 · see citing works
Vaisman (2014) · PubMed · doi:10.3275/8810 · Cited by 49 · see citing works
Castellana, M., Castellana, C., Giovanella, L., & Trimboli, P. (2020) · Endocrine · doi:10.1007/s12020-019-02185-4 · Cited by 41 · see citing works
Hepp, Z., Lage, M. J., Espaillat, R., & Gossain, V. V. (2018) · Journal of Medical Economics · doi:10.1080/13696998.2018.1484749 · Cited by 37 · see citing works
Skelin, M., Lucijanić, T., Liberati-Čizmek, A.-M., Klobučar, S. M., Lucijanić, M., Jakupović, L., Bakula, M., Lončar, J. V., Marušić, S., Matić, T., et al. (2018) · Endocrine · doi:10.1007/s12020-018-1686-1 · Cited by 31 · see citing works
Pang, X., Pu, T., Xu, L., & Sun, R. (2020) · Clinical Endocrinology · doi:10.1111/cen.14172 · Cited by 26 · see citing works
Berg, J. A., & Mayor, G. H. (1992) · The Journal of Clinical Pharmacology · doi:10.1177/009127009203201213 · Cited by 22 · see citing works
Srivastava, S., Sharma, G., Rathore, M., Chaturvedi, A., Keswani, P., Saxena, G. N., Singh, A., & Sharma, R. M. (2018) · PubMed · Cited by 10 · see citing works
Evaluation of evening versus morning levothyroxine intake in elderly (MONIALE)
Giassi, K. D. S., Piccoli, V., Rodrigues, T. D. C., & de Mello, R. G. B. (2019) · Trials · doi:10.1186/s13063-019-3816-3 · Cited by 5 · see citing works
Self-citationTiming of Levothyroxine in the Treatment of Primary Hypothyroidism
Ahmed, J. H., AL-Emara, Z., & Mansour, A. A. (2015) · Journal of Advances in Medicine and Medical Research · doi:10.9734/bjmmr/2016/22757 · Cited by 5 · see citing works
The Effect of Bedtime or Morning Intake of Levothyroxine in Patients with Hypothyroidism
Apaydın, M. (2018) · Global Journal of Endocrinological Metabolism · doi:10.31031/gjem.2018.01.000513 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Centanni, M., Duntas, L., Feldt-Rasmussen, U., Koehrle, J., Peeters, R. P., Razvi, S., Trimboli, P., & Virili, C. (2025) · European Thyroid Journal · doi:10.1530/etj-25-0123 · Cited by 38 · see citing works
“A randomized crossover trial in 201 older patients (60 years or older) did not detect any signi fi cant differences in the mean TSH levels between an hour before breakfast administration versus an hour after evening meal dosing regimen (43).”
- Authors
- de Mello, R. B., Giassi, K., Stahl, G., Machado Assis, M. L., Flores, M. S., de Lima, B. C., Piccoli, V., & da Costa Rodrigues, T.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- Venue
- Frontiers in Medicine
- Publisher
- Frontiers Media SA
- Published
- 2022-06-23
- Volume
- 9
- Pages
- 828762-828762
- ISSN
- 2296-858X (ISSN-L)
- PMC
- PMC9261378
- OpenAlex
- W4283375740
- Cited by
- 9
- References
- 31
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 1
- FWCI
- 1.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Hospital de Clínicas de Porto Alegre
- Universidade Federal do Rio Grande do Sul
- Fundação Instituto de Pesquisas Econômicas
- 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, timing of drug administration, bedtime dosing, morning dosing, older adults, thyroid-stimulating hormone, primary hypothyroidism
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
