Analysis of dose-TSH response effect of levothyroxine soft-gel formulation
Open accessAbstract
Background: Hypothyroidism is treated with daily levothyroxine (LT4). In recent years, soft gel caps of LT4 (LT4-C) have been commercialized, and their performance has been optimized. Since guidelines recommend dose LT4 according to the tablet preparation efficacy, the present study was undertaken to obtain data about the daily requirement, normalized per body weight, of LT4-C. Methods: Patients undergoing LT4-C after total thyroidectomy and radioiodine treatment for differentiated thyroid carcinoma were selected. There was no specific indication of suppression of TSH (i.e., <0.5 or <0.1 mIU/L). Patients were required to maintain a stable LT4 dose during the study period. Patients with interfering factors were excluded from this study. Results: Thirty patients were enrolled (18 females and 12 males; median age, 50 years; median body weight, 71 kg; median LT4-C dose, 1.71 µg/kg/day). The analysis of patient age did not reveal any differences. The LT4-C dose correlated with free-T4 p = 0.03), but not with TSH (p = 0.42) and free-T3 (p = 0.13). TSH was <1.0 mIU/L in 90% of the cases. The LT4-C dose-TSH response effect was analysed by probit regression model: the probability to achieve TSH <1.0 mIU/l was 99% with a dose of 1.84 (95%CI 1.57-2.12) µg/kg/day, 75% with a dose of 1.38 µg/kg/day (95%CI 1.17-1.59), and 50% with a dose of 1.20 (95%CI 0.96-1.43). At ROC curve analysis, the most accurate cut-off of LT4-C dose to achieve TSH <1.0 mIU/l was 1.53 ug/kg/day with 70% sensitivity and 100% specificity. Conclusions: Athyreotic patients can be initially treated with an LT4-C dose lower than previously stated. Therefore, further prospective studies are warranted.
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?
Athyreotic patients can be initially treated with an SG dose lower than previously stated for tablet preparation.
“Not surprisingly, it has been demonstrated that athyreotic patients can be initially treated with an SG dose lower than previously stated for tablet preparation (124).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [124]
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
von Elm, E., Altman, D. G., Egger, M., Pocock, S. J., Gøtzsche, P. C., & Vandenbroucke, J. P. (2007) · The Lancet · doi:10.1016/s0140-6736(07)61602-x · Cited by 21,320 · see citing works
Haugen, B. R., Alexander, E. K., Bible, K. C., Doherty, G. M., Mandel, S. J., Nikiforov, Y. E., Pacini, F., Randolph, G. W., Sawka, A. M., Schlumberger, M., et al. (2016) · Thyroid® · doi:10.1089/thy.2015.0020 · Cited by 16,535 · see citing works
Kirk, J. M. W., MacDonald, A., Lavender, P., Dean, J. M., & Rubin, G. (2017) · Biomedicine Hub · doi:10.1159/000480347 · Cited by 3,901 · 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 · cited 3× · see citing works
“The analysis of LT4-C requirement in elderly patients should con fi rm that the LT4 need is lower, even if it is not statistically signi fi cant due to the low number of patients and the slightly lower median value of median TSH in the elderly compared to younger patients (3, 21).”
BackgroundResultInfluentialMedication Adherence: WHO Cares?
Brown, M. T., & Bussell, J. K. (2011) · Mayo Clinic Proceedings · doi:10.4065/mcp.2010.0575 · Cited by 1,928 · see citing works
Malfertheiner, P., Camargo, M. C., El-Omar, E. M., Liou, J., Peek, R. M., Schulz, C., Smith, S. I., & Suerbaum, S. (2023) · Nature Reviews Disease Primers · doi:10.1038/s41572-023-00431-8 · Cited by 1,285 · see citing works
Treatment with thyroid hormone
Biondi, B., & Wartofsky, L. (2014) · Endocrine Reviews · doi:10.1210/er.2013-1083 · Cited by 259 · 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
Self-citationPabla, D., Akhlaghi, F., & Zia, H. (2009) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.10.008 · Cited by 124 · see citing works
Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report
Centanni, M., Benvenga, S., & Sachmechi, I. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0706-y · Cited by 113 · see citing works
Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers
Jonklaas, J., & Razvi, S. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30371-1 · Cited by 100 · cited 1× · see citing works
“…in fl ammatory diseases, post-bariatric surgery, etc.); 3) patients featuring major and/or chronic disorders (i.e., severe non-communicable diseases, obesity, major depression, infections); 4) pregnant or lactating patients; 5) patients recently undergone radiological examination (10, 21, 24).”
BackgroundLevothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient’s Lifetime
Duntas, L. H., & Jonklaas, J. (2019) · Advances in Therapy · doi:10.1007/s12325-019-01078-2 · Cited by 94 · see citing works
Gastric juice acidity in upper gastrointestinal diseases
Lu, P.-J. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i43.5496 · Cited by 88 · see citing works
Thyroxine softgel capsule in patients with gastric-related T4 malabsorption
Santaguida, M. G., Virili, C., Duca, S. C. D., Cellini, M., Gatto, I., Brusca, N., De Vito, C., Gargano, L., & Centanni, M. (2015) · Endocrine · doi:10.1007/s12020-014-0476-7 · Cited by 68 · see citing works
Virili, C., Giovanella, L., Fallahi, P., Antonelli, A., Santaguida, M. G., Centanni, M., & Trimboli, P. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00010 · Cited by 61 · see citing works
The Burden of Hormonal Disorders: A Worldwide Overview With a Particular Look in Italy
Crafa, A., Calogero, A. E., Cannarella, R., Mongioì, L. M., Condorelli, R. A., Greco, E. A., Aversa, A., & Vignera, S. L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.694325 · Cited by 59 · see citing works
Levothyroxine therapy in gastric malabsorptive disorders
Virili, C., Brusca, N., Capriello, S., & Centanni, M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.621616 · Cited by 52 · see citing works
Ito, M., Miyauchi, A., Kang, S., Hisakado, M., Yoshioka, W., Ide, A., Kudo, T., Nishihara, E., Kihara, M., Ito, Y., et al. (2015) · European Journal of Endocrinology · doi:10.1530/eje-15-0138 · Cited by 51 · see citing works
Consequences of undertreatment of hypothyroidism
Feldt‐Rasmussen, U., Effraimidis, G., Bliddal, S., & Klose, M. (2023) · Endocrine · doi:10.1007/s12020-023-03460-1 · Cited by 47 · see citing works
Novel thyroxine formulations: a further step toward precision medicine
Virili, C., Trimboli, P., & Centanni, M. (2019) · Endocrine · doi:10.1007/s12020-019-02049-x · Cited by 41 · 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
Niculescu, D. (2020) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2020.462 · Cited by 28 · see citing works
Different formulations of levothyroxine for treating hypothyroidism: a real-life study
Trimboli, P., Scappaticcio, L., De Bellis, A., Maiorino, M. I., Knappe, L., Esposito, K., Bellastella, G., & Giovanella, L. (2020) · International Journal of Endocrinology · doi:10.1155/2020/4524759 · Cited by 27 · see citing works
Ernst, F. R., Sandulli, W., Elmor, R., Welstead, J., Sterman, A. B., & Lavan, M. (2017) · Drugs in R&D · doi:10.1007/s40268-016-0150-z · Cited by 23 · see citing works
Levothyroxine treatment and gastric juice pH in humans: the proof of concept
Virili, C., Bruno, G., Santaguida, M. G., Gargano, L., Stramazzo, I., De Vito, C., Cicenia, A., Scalese, G., Porowska, B., Severi, C., et al. (2022) · Endocrine · doi:10.1007/s12020-022-03056-1 · Cited by 22 · see citing works
Trimboli, P., Virili, C., Centanni, M., & Giovanella, L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00118 · Cited by 21 · see citing works
Paschou, S. Α., Alevizaki, M. K., Attanasio, R., Hegedűs, L. D., Nagy, E. V., Papini, E., Perros, P., & Vryonidou, A. (2021) · HORMONES · doi:10.1007/s42000-021-00335-w · Cited by 18 · see citing works
Is levothyroxine requirement the same for tablet and soft gel formulations?
Di Donna, V., Paragliola, R. M., de Waure, C., Papi, G., Pontecorvi, A., & Corsello, S. M. (2018) · Endocrine · doi:10.1007/s12020-017-1311-8 · Cited by 17 · see citing works
Pajzsmirigyhormon-kezelési szokások Magyarországon.
Berta, E., Lengyel, I. M., Hegedűs, L. D., Papini, E., Perros, P., Negro, R., Attanasio, R., Nagy, V., & Bodor, M. (2022) · Orvosi Hetilap · doi:10.1556/650.2022.32412 · Cited by 17 · see citing works
In vivo dissolution of levothyroxine soft gel capsules
Fiorini, G., Ribichini, D., Pasquali, R., & Vaira, D. (2016) · Internal and Emergency Medicine · doi:10.1007/s11739-016-1526-3 · Cited by 14 · see citing works
Increased fT4 concentrations in patients using levothyroxine without complete suppression of TSH
Jansen, H. I., Bult, M., Bisschop, P. H. L. T., Boelen, A., Heijboer, A. C., & Hillebrand, J. J. (2023) · Endocrine Connections · doi:10.1530/ec-22-0538 · Cited by 14 · see citing works
Investigating the influence of excipients on the stability of levothyroxine sodium pentahydrate
Kaur, N., & Suryanarayanan, R. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00217 · Cited by 13 · see citing works
Seeking optimization of LT4 treatment in patients with differentiated thyroid cancer
Stramazzo, I., Capriello, S., Antonelli, A., Fallahi, P., Centanni, M., & Virili, C. (2022) · HORMONES · doi:10.1007/s42000-022-00376-9 · Cited by 9 · see citing works
Self-citationDaily requirement of softgel thyroxine is independent from gastric juice pH
Virili, C., Capriello, S., Stramazzo, I., Brusca, N., Santaguida, M. G., Gargano, L., Bagaglini, M. F., Bruno, G., Severi, C., & Centanni, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1002583 · Cited by 8 · see citing works
(2019) · doi:10.26420/annalsthyroidres · Cited by 3 · 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
“Not surprisingly, it has been demonstrated that athyreotic patients can be initially treated with an SG dose lower than previously stated for tablet preparation (124).”
Chiardi, I., Croce, L., Caccavale, P., Bertini, J., Coperchini, F., Magri, F., Cappelli, C., Trimboli, P., & Rotondi, M. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf417 · Cited by 4 · see citing works
- Authors
- Trimboli, P., Piticchio, T., Dadda, Z., Stramazzo, I., Gamarra, E., Ruinelli, L., & Virili, C.
- Affiliations
- Ospedale regionale di Lugano (CH)
- University of Catania (IT)
- Università della Svizzera italiana (CH)
- Sapienza University of Rome (IT)
- Corresponding author
- Trimboli, Pierpaolo
- Piticchio, Tommaso
- ORCID
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2024-02-21
- Volume
- 15
- Pages
- 1340204-1340204
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC10915021
- OpenAlex
- W4392001757
- Cited by
- 2
- References
- 35
- Citations by year
- 2025: 2
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (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
- levothyroxine, dose-response relationship, thyroid-stimulating hormone, hypothyroidism, differentiated thyroid cancer, total thyroidectomy, radioiodine ablation, free thyroxine, probit model
- MeSH terms
- Body Weight, Female, Humans, Hypothyroidism, Iodine Radioisotopes, Male, Middle Aged, Thyrotropin, Thyroxine
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
