The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism
Abstract
A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.
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In the citing paper
“The absorption of an orally administered dose of LT4 is about 70%-80% under optimum fasting conditions (38,119,120).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Steady-state levels of T4 and TSHaregenerally achieved in 6 weeks (approximately five to six half-lives) after initiation of therapy (38).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Moreover, in athyreotic individuals treated with LT4 to achieve a normal serum TSH, the serum FT4 is usually higher and the serum T3 is either normal (38,39) or lower than the values seen in normal individuals (39-43).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Based on body weight, hypothyroid patients with minimal endogenous thyroid function require LT4 doses of 1.6-1.8 l g/kg of actual body weight (38,47,212,213,215-217,226,227), although some studies estimate higher doses of 2.0-2.1 l g/kg for some patient groups (212,213,226).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“LT4 doses in thyroid cancer patients requiring TSH suppression are generally higher and on the order of 2.1-2.7 l g/kg (38,212,215).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“The peripheral conversion of T4 into T3 makes it possible to achieve normal serum T3 concentrations in humans treated with L-T4 [26] ,”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“Normalization of serum TSH and T3 concentrations is achieved with L-T4 therapy at the expense of higher serum free T4 concentrations than normal [26,27] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“To obtain serum TSH values similar to controls during L-T4 monotherapy, serum free T4 concentrations higher than controls are required at serum free T3 values similar to those in controls [26,27] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“As a consequence, in daily clinical practice mental health providers in community settings do not ask about medical issues or test for them because of insufficient consideration of the physical health needs, or shortage or time/ resources.315”
From The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness (2019) · cites this paper as [315]
In the citing paper
“In a previous study involving 19 patients, the TSH levels were normalized only when patients’ T3 levels were not significantly different from those of controls (159).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [159]
In the citing paper
“While earlier studies already hinted that TSH normalization may not suffice to guarantee a normal serum T3, the more detailed inter-relationships have only recently been analyzed (9, 122, 196–199).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [196]
Citations
Cites
Thyroid-Pituitary Interaction: Feedback Regulation of Thyrotropin Secretion by Thyroid Hormones
Bleich, H. L., Moore, M. J., & Larsen, P. R. (1982) · New England Journal of Medicine · doi:10.1056/nejm198201073060107 · Cited by 357
Oppenheimer, J. H., Squee, R., Surks, M. I., & Hauer, H. (1963) · Journal of Clinical Investigation · doi:10.1172/jci104862 · Cited by 255
Surks, M. I., Schadlow, A. R., Stock, J. M., & Oppenheimer, J. H. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107244 · Cited by 223
SILVA, J. E., DICK, T. E., & LARSEN, P. R. (1978) · Endocrinology · doi:10.1210/endo-103-4-1196 · Cited by 189
Surks, M. I., Schadlow, A. R., & Oppenheimer, J. H. (1972) · Journal of Clinical Investigation · doi:10.1172/jci107137 · Cited by 188
Replacement Dosage of L-Thyroxine in Hypothyroidism: A Re-Evaluation
Stock, J. M., Surks, M. I., & Oppenheimer, J. H. (1974) · New England Journal of Medicine · doi:10.1056/nejm197403072901001 · Cited by 184
Self-citationAutoantibodies Against Thyroid Hormones or lodothyronine
Sakata, S., NAKAMURA, S., & MIURA, K. (1985) · Annals of Internal Medicine · doi:10.7326/0003-4819-103-4-579 · Cited by 174
Pulsatile secretion of thyrotropin in man
GREENSPAN, S. L., KLIBANSK, A., SCHQENFELD, D., & RIDGWAY, E. C. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-3-661 · Cited by 140
Oppenheimer, J. H., Schwartz, H. L., & Surks, M. I. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-41-2-319 · Cited by 137
CIRCADIAN VARIATIONS OF SERUM THYROTROPIN LEVELS IN MAN1
Vanhaelst, L., Cauter, E. V., Degaute, J. P., & GOLSTEIN, J. (1972) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-35-3-479 · Cited by 118
Research works printed but not linked: 1
- Jacobus R, Rabinow B, Luecke J. Determination of levothyroxine sodium in the drug substance and Synthroid levothyroxine sodium tablets by reverse-phase high-performance liquid chromatography. In: Proceedings of the FDA-USP workshop on drug and reference standards for insulins, somatotropins and thyroid-axis hormones. Bethesda, Md.: U.S. Pharmacopeial Convention, 1982:487–95.
Cited by
Sorted by citations
Items 301–351 of 351
Bansal, S. (1989) · Postgraduate Medicine · doi:10.1080/00325481.1989.11704387 · Cited by 1
Dong, B. J. (1992) · Palgrave Macmillan UK eBooks · doi:10.1007/978-1-349-13175-4_71 · Cited by 1
Thyroid Hormone Replacement Therapy for Primary and Secondary Hypothyroidism
Cooper, D. S. (2003) · Humana Press eBooks · doi:10.1007/978-1-59259-375-0_7
Drug Therapy of Thyroid Autoimmune Disorders
Rodien, P., & Orgiazzi, J. (1994) · BioDrugs · doi:10.1007/bf03259266
Reassurance About Bioequivalence of Generic Thyroxine in the United Kingdom
Feek, C. M. (1993) · Clinical Research and Regulatory Affairs · doi:10.3109/10601339309014393
Traitement et surveillance de l'hypothyroïdie primitive
Schlienger, J.-L., Sapin, R., Grünenberger, F., & Pradignac, A. (1992) · La Revue de Médecine Interne · doi:10.1016/s0248-8663(05)80311-x
L-thyroxine therapy for congenital hypothyroidism and Marfan syndrome
Khanna, R., & Dixit, S. (1992) · The Indian Journal of Pediatrics · doi:10.1007/bf02821811
Camargo, R. Y. A., de Souza, J. J. S., Bezerra, A. K. M., Seidenberger, K., Tomimori, E. K., Cardia, M., Knobel, M., Brandão, L. G., & Medeiros-Neto, G. A. (2002) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302002000500006
L-T4 and L-T3 combined treatment vs L-T4 alone
Wiersinga, W. M. (2007) · Annales d Endocrinologie · doi:10.1016/j.ando.2007.06.008
Aus der Medizinischen Universitätsklinik und
Tübingen, P., & Medizin, A. I. (2005)
Tratamento do hipotiroidismo baseado em evidência
Valente, O., de Oliveira, F., & Valente, F. (2009)
Analysis of a Large Population Establishes the Linear Relationship Between Log TSH and Free T 4
Hershman, J. M. (2016) · Clinical Thyroidology · doi:10.1089/ct.2016;28.45-47
Boguszewski, C. L. (1993) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Concentration Timing of Levothyroxine Administration Affects Serum Thyrotropin
Bach-Huynh, T.-G., Nayak, B. M., Loh, J. A., Soldin, S. J., & Jonklaas, J. (2009)
Levothyroxine Therapy: When Outcomes Are Less Than Optimal-Optimizing Patient Care
Hennessey, J. V. (2016) · The Endocrine Society eBooks · doi:10.1210/mtp5.9781943550043.ch68
Baron, H. L., & SINGER, P. A. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-3291-5.50042-1
Case 14-2016: A Woman with a Thyroid Nodule and Psychosis
Delichatsios, H., & Fasano, A. (2016) · New England Journal of Medicine · doi:10.1056/nejmc1607733
Guías de práctica clínica para el tratamiento del hipotiroidismo
Brenta, G., Vaisman, M., Sgarbi, J. A., de Andrada, N. C., Bravo, P. P., Orlandi, A. M., & Graf, H. (2013)
Alternative Sequences of Thyrotropin and Free Thyroxine Assays for Routine Thyroid Function Testing
Nordyke, R. A., Reppun, T. S., Madanay, L. D., Woods, J. C., Goldstein, A. P., & Miyamoto, L. A. (2017)
Braithwaite, S. S. (2008) · Elsevier eBooks · doi:10.1016/b978-032304841-5.50063-7
Perioperative Management Endocrine Problems in Pediatric Cardiac Surgical Patients
Hashemipour, M., Dehkordi, E. H., Mostofizadeh, N., Soheilipour, F., Ghasemi, M., Mazaheri, A., & Rostampour, N. (2017) · Springer eBooks · doi:10.1007/978-3-319-44691-2_38
Solter, D., & Solter, M. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2017.11.003
Treatment of Hypothyroidism with Levothyroxine
Laan, R. F., PIETERS, G. F. F. M., Smals, A. G., & KLOPPENBORG, P. W. C. (1987) · New England Journal of Medicine · doi:10.1056/nejm198709173171216
Wood, C. L., Cole, M., Donaldson, M., Dunger, D. B., Wood, R., Morrison, N., Jns, M., Shs., P., & Cheetham, T. D. (2021) · Yearbook of pediatric endocrinology · doi:10.1530/ey.18.3.12
(2003) · Thyroid · doi:10.1089/105072503321087097
Luíz, H. V., Manita, I., & Portugal, J. (2016) · Springer eBooks · doi:10.1007/978-3-319-25871-3_7
Krátký, J. (2022) · Vnitřní lékařství · doi:10.36290/vnl.2022.010 · Cited by 1
Kim, M. (2014) · Oxford University Press eBooks · doi:10.1093/med/9780199358274.003.0047
(2006) · Elsevier eBooks · doi:10.1016/b0-44-451005-2/00977-3
Thyroid Hormone Replacement Therapy for Primary and Secondary Hypothyroidism
Cooper, D. S. (1999) · Humana Press eBooks · doi:10.1007/978-1-59259-700-0_6
IODINE AND DRUGS THAT AFFECT THYROID FUNCTION
(2009) · Elsevier eBooks · doi:10.1016/b978-0-444-53271-8.50007-7
(2015) · Elsevier eBooks · doi:10.1016/b978-0-444-53717-1.01544-4
VOLPEÉ, R. (1990) · Elsevier eBooks · doi:10.1016/b978-0-7216-2190-6.50019-4
Curry, S. H., & Wolfson, B. B. (1989) · DICP · doi:10.1177/106002808902301019
Seyffart, G. (1991) · Springer eBooks · doi:10.1007/978-94-011-3804-8_12
Greenspan, S. L., Greenspan, F. S., & Resnick, N. M. (1992) · The American Journal of Medicine · doi:10.1016/0002-9343(92)90800-q
Torres-Barea, I. M., Blanco, M. C., Coserria, C., & Aguilar‐Diosdado, M. (2012) · Medicine - Programa de Formación Médica Continuada Acreditado · doi:10.1016/s0304-5412(12)70390-6
New-Onset Heart Failure in the Setting of T4-Conversion Disorder
Chan, N. I., Pak, K., Guo, A., Singla, P., & Sayegh, M. N. (2022) · Cureus · doi:10.7759/cureus.25024
Comparative Assessment of the Physicochemical Properties of Different Brands of Levothyroxine
Sattar, A., Naveed, S., Rehman, H., Ayaz, S., Usman, R., Yasmeen, S., Razzaq, G., Qamar, F., & Sadia, H. (2022) · Journal of Hunan University Natural Sciences · doi:10.55463/issn.1674-2974.49.8.21 · Cited by 1
Fitzgerald, S. P., Bean, N. G., Falhammar, H., Hoermann, R., Kohanim, Y. K., Pohlabeln, H., & Beverborg, N. G. (2023) · Research Square · doi:10.21203/rs.3.rs-3060328/v1
Case report: severe hypoglycaemia as a late manifestation of SheehanÓ?s syndrome
Romero-Vásquez, E. R., Arteaga-Martínez, L. A., Rodríguez, G. N. L., & Ornelas-Aguirre, J. M. (2023) · Cirugía y Cirujanos (English Edition) · doi:10.24875/cirue.m20000314
Terapia dell’ipotiroidismo primitivo: un ormone o due ormoni?
Brigante, G., Ceccarini, G., Porcelli, T., Santini, F., Salvatore, D., Simoni, M., & Bartalena, L. (2024) · L Endocrinologo · doi:10.1007/s40619-024-01429-4
Thyroid and Parathyroid Transplantation
Sakr, M. F. (2024) · Springer eBooks · doi:10.1007/978-3-031-64102-2_18
Guglielmi, R., Mian, C., Andreoli, C., Bagnasco, M., Boniardi, M., Menis, E. D., Rimini, M. L. D., Tina, D., Fiorentini, G., Locantore, P., et al. (2025) · L Endocrinologo · doi:10.1007/s40619-025-01601-4
Linea guida sulla gestione terapeutica nell’adulto con ipotiroidismo primario non in gravidanza
Guglielmi, R., Mian, C., Novizio, R., Paoletta, A., Persichetti, A., Samperi, I., Scoppola, A., Bagnasco, M., Menis, E. D., Rimini, M. L. D., et al. (2025) · L Endocrinologo · doi:10.1007/s40619-025-01674-1
Uzeli, Ü. Ş., & Tutan, D. (2025) · Hitit Medical Journal · doi:10.52827/hititmedj.1705311
Mehran, L., Amouzegar, A., Foroutan, S. M., Masoumi, S., Tohidi, M., Abdi, H., Aghaei, A., Saghafinia, A. E., & Azizi, F. (2024) · Figshare · doi:10.6084/m9.figshare.26613242
Weight-based Levothyroxine Dose Calculator for Hypothyroidism in Adults
Lundholm, M. D. (2025) · Evidence to Action Official Journal of MDCalc · doi:10.65357/001c.145848
Editorial: Levothyroxine therapy in patients with hypothyroidism, volume II
Antonelli, A., & Miccoli, P. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1940738
Metadata
- Authors
- Fish, L. H., Schwartz, H. L., Cavanaugh, J., Steffes, M. W., Bantle, J. P., & Oppenheimer, J. H.
- ORCID
- Steffes, Michael W.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1987-03-26
- Volume
- 316
- Issue
- 13
- Pages
- 764-770
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2324164337
- Cited by
- 353
- References
- 18
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 13 · 2017: 14 · 2016: 19 · 2015: 13 · 2014: 13 · 2013: 9 · 2012: 17
- FWCI
- 11.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AM-19-812, 2t32am007203-09, 1f32am007586-01)
- 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, drug formulation change, bioavailability, gastrointestinal absorption, drug metabolism, thyroid-stimulating hormone, serum triiodothyronine, serum thyroxine, dose titration
- MeSH terms
- Biological Availability, Feedback, Humans, Hypothyroidism, Intestinal Absorption, Pituitary Gland, Anterior, Tablets, Thyrotropin, Thyroxine, Triiodothyronine
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