Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism

Fish, Lisa H.; Schwartz, Harold L.; Cavanaugh, John; Steffes, Michael W.; Bantle, John P.; Oppenheimer, Jack H.

doi:10.1056/nejm198703263161302

Cited by 353Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism

Fish, Lisa H., Schwartz, Harold L., Cavanaugh, John, Steffes, Michael W., Bantle, John P., Oppenheimer, Jack H.·1987·New England Journal of Medicine

DOI 10.1056/nejm198703263161302

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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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The absorption of an orally administered dose of LT4 is about 70%-80% under optimum fasting conditions.
“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]
Steady-state levels of T4 and TSH are generally achieved 6 weeks after initiation of LT4 therapy.
“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 athyreotic individuals treated with LT4 to achieve a normal serum TSH, serum FT4 is usually higher than in normal individuals.
“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]
Hypothyroid patients with minimal endogenous thyroid function require LT4 doses of 1.6-1.8 μg/kg actual body weight.
“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]
Thyroid cancer patients requiring TSH suppression generally require LT4 doses of 2.1-2.7 μg/kg.
“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]

The peripheral conversion of T4 into T3 makes it possible to achieve normal serum T3 concentrations in humans treated with L-T4.
“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]
Normalization of serum TSH and T3 concentrations is achieved with L-T4 therapy at the expense of higher serum free T4 concentrations than normal.
“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]
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.
“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 daily clinical practice, mental health providers in community settings do not ask about medical issues or test for them because of insufficient consideration of physical health needs or shortage of time and resources.
“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 a previous study involving 19 patients, TSH levels were normalized only when patients' T3 levels were not significantly different from those of controls.
“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]
TSH normalization may not suffice to guarantee a normal serum T3.
“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]

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 · see citing works
BINDING OF THYROXINE BY SERUM PROTEINS EVALUATED BY EQUILIBRIUM DIALYSIS AND ELECTROPHORETIC TECHNIQUES. ALTERATIONS IN NON-THYROIDAL ILLNESS*
Oppenheimer, J. H., Squee, R., Surks, M. I., & Hauer, H. (1963) · Journal of Clinical Investigation · doi:10.1172/jci104862 · Cited by 255 · see citing works
Determination of iodothyronine absorption and conversion of L-thyroxine (T4) to L-triiodothyronine (T3) using turnover rate techniques
Surks, M. I., Schadlow, A. R., Stock, J. M., & Oppenheimer, J. H. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107244 · Cited by 223 · see citing works
The Contribution of Local Tissue Thyroxine Monodeiodination to the Nuclear 3,5,3′- Triiodothyronine in Pituitary, Liver, and Kidney of Euthyroid Rats*
SILVA, J. E., DICK, T. E., & LARSEN, P. R. (1978) · Endocrinology · doi:10.1210/endo-103-4-1196 · Cited by 189 · see citing works
A New Radioimmunoassay for Plasma l-Triiodothyronine: Measurements in Thyroid Disease and in Patients Maintained on Hormonal Replacement
Surks, M. I., Schadlow, A. R., & Oppenheimer, J. H. (1972) · Journal of Clinical Investigation · doi:10.1172/jci107137 · Cited by 188 · see citing works
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 · see citing works
Autoantibodies 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 · see citing works
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 · see citing works
Determination of Common Parameters of Iodothyronine Metabolism and Distribution in Man by Noncompartmental Analysis
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 · see citing works
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 · see citing works
Absorption of oral thyroxine in man
HAYS, M. T. (1968) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-28-6-749 · Cited by 111 · see citing works
Serum Thyroid Hormone and Thyrotropin Levels in Subjects from Endemic Goiter Regions of New Guinea
CHOPRA, I. J., HERSHMAN, J. M., & HORNABROOK, R. W. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-40-2-326 · Cited by 106 · see citing works
Effects of Replacement Doses of Sodium-L-Thyroxine on the Peripheral Metabolism of Thyroxine and Triiodothyronine in Man
Braverman, L. E., Vagenakis, A. G., Downs, P., Foster, A. E., Sterling, K., & Ingbar, S. H. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107265 · Cited by 98 · see citing works
L -Thyroxine Dosage: A Reevaluation of Therapy with Contemporary Preparations
Hennessey, J. V., EVAUL, J. E., TSENG, Y.-C., BURMAN, K. D., & WARTOFSKY, L. (1986) · Annals of Internal Medicine · doi:10.7326/0003-4819-105-1-11 · Cited by 92 · see citing works
Oral Thyroxine: Variation in Biologic Action and Tablet Content
Sawin, C. T., SURKS, M. I., LONDON, M., RANGANATHAN, C., & Larsen, P. R. (1984) · Annals of Internal Medicine · doi:10.7326/0003-4819-100-5-641 · Cited by 47 · see citing works
Peripheral Metabolism of Thyroid Hormones in Man, I. Direct Measurement of the Conversion Rate of Thyroxine to 3,5,3'-Triiodothyronine (T3) and Determination of the Peripheral and Thyroidal Production of T3
BIANCHI, R., Mariani, G., Molea, N., Vitek, F., Cazzuola, F., Carpi, A., Mazzuca, N., & Toni, M. G. (1983) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-56-6-1152 · Cited by 43 · see citing works
Evaluation of Triiodothyronine (T3) Kinetics in Normal Subjects, in Hypothyroid, and Hyperthyroid Patients Using Specific Antiserum for the Determination of Labeled T3in Plasma
BIANCHI, R., Zucchelli, G. C., Giannessi, D., PILO, A., Mariani, G., Carpi, A., Toni, M., & Cazzuola, F. (1978) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-46-2-203 · Cited by 40 · see citing works
Potency of Levothyroxine Products
Stoffer, S. S. (1984) · JAMA · doi:10.1001/jama.1984.03340290049020 · Cited by 28 · see citing works

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Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement
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
“Steady-state levels of T4 and TSH are generally achieved in 6 weeks (approximately five to six half-lives) after initiation of therapy (38).”
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The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness
Firth, J., Siddiqi, N., Koyanagi, A., Siskind, D., Rosenbaum, S., Galletly, C., Allan, S., Caneo, C., Carney, R., Carvalho, A. F., et al. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30132-4 · Cited by 1,531 · see citing works
Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567 · see citing works
Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053 · see citing works
European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism
Léger, J., Olivieri, A., Donaldson, M., Torresani, T., Krude, H., van Vliet, G., Polak, M., Butler, G., & on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, A. T. C. H. C. C. G. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1891 · Cited by 569 · see citing works
Hypothyroidism
Roberts, C. G., & Ladenson, P. W. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15696-1 · Cited by 567 · see citing works
2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism
Wiersinga, W. M., Duntas, L., Fadeyev, V., Nygaard, B., & Vanderpump, M. P. J. (2012) · European Thyroid Journal · doi:10.1159/000339444 · Cited by 427 · see citing works
Thyroxine in Goiter, <i>Helicobacter pylori</i> Infection, and Chronic Gastritis
Centanni, M., Gargano, L., Canettieri, G., Viceconti, N., Franchi, A., Fave, G. D., & Annibale, B. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa043903 · Cited by 329 · see citing works
The Thyrotropin Reference Range Should Remain Unchanged
Surks, M. I., Goswami, G., & Daniels, G. H. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0170 · Cited by 287 · see citing works
Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.
Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118353 · Cited by 287 · see citing works
Benefits of Thyrotropin Suppression Versus the Risks of Adverse Effects in Differentiated Thyroid Cancer
Biondi, B., & Cooper, D. S. (2010) · Thyroid · doi:10.1089/thy.2009.0311 · Cited by 286 · see citing works
Scientific Opinion on Dietary Reference Values for iodine
EFSA Panel on Dietetic Products, N. A. A. (. (2014) · EFSA Journal · doi:10.2903/j.efsa.2014.3660 · Cited by 267 · 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
Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.
Escobar-Morreale, H. F., del Rey, F. E., Obregón, M. J., & de Escobar, G. M. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641203 · Cited by 261 · see citing works
Resistance to Thyroid Hormone
Weiss, R. E., & Refetoff, S. (2000) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1010072605757 · Cited by 257 · see citing works
Long-term L-thyroxine therapy is associated with decreased hip bone density in premenopausal women.
Paul, T. L., Kerrigan, J., Kelly, A., Braverman, L., & Baran, D. (1988) · Journal of the American Medical Association (JAMA) · doi:10.1001/jama.1988.03720210027023 · Cited by 241 · see citing works
Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer
McGriff-Lee, N. J., Csákó, G., Gourgiotis, L., Guthrie, L. C., Pucino, F., & Sarlis, N. J. (2002) · Annals of Medicine · doi:10.1080/078538902321117760 · Cited by 243 · see citing works
High Frequency of and Factors Associated with Thyroid Hormone Over-Replacement and Under-Replacement in Men and Women Aged 65 and Over
Somwaru, L. L., Arnold, A. M., Joshi, N., Fried, L. P., & Cappola, A. R. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1696 · Cited by 239 · see citing works
Lean Body Mass Is a Major Determinant of Levothyroxine Dosage in the Treatment of Thyroid Diseases
Santini, F., Pinchera, A., Marsili, A., Ceccarini, G., Castagna, M. G., Valeriano, R., Giannetti, M., Taddei, D., Centoni, R., Scartabelli, G., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1306 · Cited by 226 · see citing works
The Relationship Between TSH and Free T4 in a Large Population Is Complex and Nonlinear and Differs by Age and Sex
Hadlow, N. C., Rothacker, K. M., Wardrop, R., Brown, S. J., Lim, E. M., & Walsh, J. P. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4223 · Cited by 203 · see citing works
Hypothyroidism: etiology, diagnosis, and management
Almandoz, J. P., & Gharib, H. (2012) · Medical Clinics of North America · doi:10.1016/j.mcna.2012.01.005 · Cited by 216 · see citing works
Does treatment withl-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism?
Jaeschke, R., Guyatt, G. H., Gerstein, H. C., Patterson, C., Molloy, W., Cook, D., Harper, S., Griffith, L. E., & Carbotte, R. M. (1996) · Journal of General Internal Medicine · doi:10.1007/bf02598988 · Cited by 216 · see citing works
Triiodothyronine Levels in Athyreotic Individuals During Levothyroxine Therapy
Jonklaas, J. (2008) · JAMA · doi:10.1001/jama.299.7.769 · Cited by 216 · see citing works
Combined Thyroxine/Liothyronine Treatment Does Not Improve Well-Being, Quality of Life, or Cognitive Function Compared to Thyroxine Alone: A Randomized Controlled Trial in Patients with Primary Hypothyroidism
Walsh, J. P., Shiels, L., Lim, E. M., Bhagat, C. I., Ward, L. C., Stuckey, B. G. A., Dhaliwal, S. S., Chew, G. T., Bhagat, M. C., & Cussons, A. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030249 · Cited by 210 · see citing works
European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism
Léger, J., Olivieri, A., Donaldson, M., Torresani, T., Krude, H., van Vliet, G., Polak, M., Butler, G., & on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, A. T. C. H. C. C. G. (2014) · Hormone Research in Paediatrics · doi:10.1159/000358198 · Cited by 208 · 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
Overt and Subclinical Hypothyroidism
Khandelwal, D., & Tandon, N. (2011) · Drugs · doi:10.2165/11598070-000000000-00000 · Cited by 199 · see citing works
Bioequivalence of Generic and Brand-name Levothyroxine Products in the Treatment of Hypothyroidism
Dong, B. J. (1997) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1997.03540390035032 · Cited by 185 · see citing works
Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing <scp>l</scp>-Thyroxine plus Liothyronine with <scp>l</scp>-Thyroxine Alone
Escobar-Morreale, H. F., Botella-Carretero, J. I., Gómez-Bueno, M., Galán, J. M., Barrios, V., & Sancho, J. (2005) · Annals of Internal Medicine · doi:10.7326/0003-4819-142-6-200503150-00007 · Cited by 182 · see citing works
Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?
Peterson, S. J., McAninch, E. A., & Bianco, A. C. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2660 · Cited by 182 · see citing works
Management of hypothyroidism in adults
Vaidya, B., & Pearce, S. H. S. (2008) · BMJ · doi:10.1136/bmj.a801 · Cited by 178 · see citing works
A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism
Colucci, P., Yue, C. S., Ducharme, M., Benvenga, S., Principal Scientist, L. A. C. I., Principal Scientist, L. A. C. I. A. P. C., President and CEO, L. A. C. I., & Professor of Medicine, D. (2010) · European Endocrinology · doi:10.17925/ee.2013.09.01.40 · Cited by 167 · see citing works
Treatment of Hypothyroidism with Combinations of Levothyroxine plus Liothyronine
Escobar-Morreale, H. F., Botella-Carretero, J. I., del Rey, F. E., & de Escobar, G. M. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0184 · Cited by 160 · see citing works
Clinical practice guidelines for the management of hypothyroidism
Brenta, G., Vaisman, M., Sgarbi, J. A., Bergoglio, L., de Andrada, N. C., Bravo, P. P., Orlandi, A. M., & Graf, H. (2013) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302013000400003 · Cited by 161 · see citing works
Hyperthyroidism, Thyroid Hormone Therapy, and Bone
Ross, D. S. (1994) · Thyroid · doi:10.1089/thy.1994.4.319 · Cited by 146 · see citing works
The Starting Dose of Levothyroxine in Primary Hypothyroidism Treatment: A Prospective, Randomized, Double-blind Trial
Roos, A., Linn-Rasker, S. P., van Domburg, R. T., Tijssen, J. P., & Berghout, A. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.15.1714 · Cited by 150 · see citing works
Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer
Burmeister, L. A., Goumaz, M., Mariash, C. N., & Oppenheimer, J. H. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.75.2.1639933 · Cited by 150 · see citing works
Thyroid Hormone Replacement Therapy
Wiersinga, W. M. (2001) · Hormone Research in Paediatrics · doi:10.1159/000048140 · Cited by 150 · see citing works
FINE ADJUSTMENT OF THYROXINE REPLACEMENT DOSAGE: COMPARISON OF THE THYROTROPHIN RELEASING HORMONE TEST USING A SENSITIVE THYROTROPHIN ASSAY WITH MEASUREMENT OF FREE THYROID HORMONES AND CLINICAL ASSESSMENT
CARR, D., MCLEOD, D. T., PARRY, G., & THORNES, H. M. (1988) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1988.tb01219.x · Cited by 210 · see citing works
Hypothyroidism
Devdhar, M., Ousman, Y. H., & Burman, K. D. (2007) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2007.04.008 · Cited by 146 · see citing works
Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00177 · Cited by 143 · see citing works
Does Postoperative Thyrotropin Suppression Therapy Truly Decrease Recurrence in Papillary Thyroid Carcinoma? A Randomized Controlled Trial
Sugitani, I., & Fujimoto, Y. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0161 · Cited by 141 · see citing works
SERUM THYROID-STIMULATING HORMONE MEASUREMENT FOR ASSESSMENT OF THYROID FUNCTION AND DISEASE
Ross, D. S. (2001) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70186-9 · Cited by 140 · see citing works
Influence of Drugs on Thyroid Function in Dogs
Daminet, S., & Ferguson, D. C. (2003) · Journal of Veterinary Internal Medicine · doi:10.1111/j.1939-1676.2003.tb02467.x · Cited by 137 · see citing works
Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients
Alexopoulou, O., Beguin, C., De Nayer, P., & Maiter, D. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500001 · Cited by 135 · see citing works
The Use and Limitations of a Chemiluminescent Thyrotropin Assay as a Single Thyroid Function Test in an Out-Patient Endocrine Clinic*
ROSS, D. S., DANIELS, G. H., & GOUVEIA, D. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-3-764 · Cited by 126 · see citing works
Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind, Crossover Trial of Liothyronine <i>Versus</i> Levothyroxine
Celi, F. S., Zemskova, M., Linderman, J. D., Smith, S., Drinkard, B., Sachdev, V., Skarulis, M. C., Kozlosky, M., Csako, G., Costello, R., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1329 · Cited by 125 · see citing works
Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism?
Biondi, B., & Wartofsky, L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3399 · Cited by 124 · see citing works
Health Status, Psychological Symptoms, Mood, and Cognition in L-Thyroxine-Treated Hypothyroid Subjects
Samuels, M. H., Schuff, K. G., Carlson, N. E., Carello, P., & Janowsky, J. S. (2007) · Thyroid · doi:10.1089/thy.2006.0252 · Cited by 124 · see citing works
Hypothyroidism in the Elderly: Pathophysiology, Diagnosis and Treatment
Laurberg, P., Andersen, S., Pedersen, I. B., & Carl, A. B. (2005) · Drugs & Aging · doi:10.2165/00002512-200522010-00002 · Cited by 141 · see citing works
Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism
Wiersinga, W. M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.258 · Cited by 114 · see citing works
Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine
Slawik, M., Klawitter, B., Meiser, E., Schories, M., Zwermann, O., Borm, K., Peper, M., Lubrich, B., Hug, M. J., Nauck, M., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0297 · Cited by 113 · see citing works
FREE THYROID HORMONE MEASUREMENT
Stockigt, J. (2001) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70187-0 · Cited by 110 · see citing works
The Use and Misuse of Thyroid Hormone*
Roti, E., Minelli, R., Gardini, E., & Braverman, L. E. (1993) · Endocrine Reviews · doi:10.1210/edrv-14-4-401 · Cited by 106 · see citing works
Sucralfate causes malabsorption of L-thyroxine
Sherman, S. I., Tielens, E. T., & Ladenson, P. W. (1994) · The American Journal of Medicine · doi:10.1016/0002-9343(94)90093-0 · Cited by 105 · see citing works
Correlations of Free Thyroid Hormones Measured by Tandem Mass Spectrometry and Immunoassay with Thyroid-Stimulating Hormone across 4 Patient Populations
Jonklaas, J., Janicic, N., Soldin, O. P., & Soldin, S. J. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2008.118752 · Cited by 101 · see citing works
Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients
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
Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis
McAninch, E. A., Rajan, K. B., Miller, C. H., & Bianco, A. C. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01361 · Cited by 94 · see citing works
Levothyroxine Replacement Doses Are Affected by Gender and Weight, But Not Age
Devdhar, M., Drooger, R., Pehlivanova, M., Singh, G., & Jonklaas, J. (2011) · Thyroid · doi:10.1089/thy.2011.0029 · Cited by 90 · see citing works
Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle
Hennemann, G., Docter, R., Visser, T. J., Postema, P. T., & Krenning, E. P. (2004) · Thyroid · doi:10.1089/105072504323030924 · Cited by 90 · see citing works
<scp>l</scp>-Thyroxine Requirement in Patients with Autoimmune Hypothyroidism and Parietal Cell Antibodies
Checchi, S., Montanaro, A., Pasqui, L., Ciuoli, C., De Palo, V., Chiappetta, M. C., & Pacini, F. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1544 · Cited by 89 · see citing works
Pseudomalabsorption of levothyroxine
Ain, K. B. (1991) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1991.03470150090036 · Cited by 100 · see citing works
Thyrotoxicosis due to Ingestion of Excess Thyroid Hormone*
Cohen, J. H., INGBAR, S. H., & Braverman, L. E. (1989) · Endocrine Reviews · doi:10.1210/edrv-10-2-113 · Cited by 88 · see citing works
Bone mineral density in postmenopausal women treated with L-thyroxine.
Adlin, E., Maurer, A. H., Marks, A. D., & Channick, B. J. (1991) · American Journal of Medicine · doi:10.1016/0002-9343(91)90577-k · Cited by 96 · see citing works
Generic and Brand-Name <scp>l</scp> -Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism
Carswell, J. M., Gordon, J. H., Popovsky, E., Hale, A., & Brown, R. S. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3125 · Cited by 83 · see citing works
TSH normalization in bariatric surgery patients after the switch from L-Thyroxine in tablet to an oral liquid formulation
Fallahi, P., Ferrari, S. M., Camastra, S., Politti, U., Ruffilli, I., Vita, R., Navarra, G., Benvenga, S., & Antonelli, A. (2017) · Obesity Surgery · doi:10.1007/s11695-016-2247-4 · Cited by 81 · see citing works
Subclinical thyroid dysfunction and cardiovascular consequences: An alarming wake-up call?
Manolis, A. S., Manolis, T. A., Melita, H., & Manolis, A. S. (2019) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2019.02.011 · Cited by 81 · see citing works
Controversies in the Management of Low-Risk Differentiated Thyroid Cancer
Haymart, M. R., Esfandiari, N. H., Stang, M. T., & Sosa, J. A. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00067 · Cited by 79 · see citing works
Thyroid hormone and the gut
Hays, M. T. (1988) · Endocrine Research · doi:10.3109/07435808809032986 · Cited by 94 · see citing works
Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?
Ettleson, M. D., & Bianco, A. C. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa430 · Cited by 75 · see citing works
Thyroid Disorders
Gessl, A., Lemmens‐Gruber, R., & Kautzky‐Willer, A. (2012) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-30726-3_17 · Cited by 77 · see citing works
Sex and Age Differences in Levothyroxine Dosage Requirement
Jonklaas, J. (2010) · Endocrine Practice · doi:10.4158/ep09257.or · Cited by 72 · see citing works
Using Body Mass Index to Predict Optimal Thyroid Dosing after Thyroidectomy
Ojomo, K. A., Schneider, D. F., Reiher, A. E., Lai, N. B., Schaefer, S. C., Chen, H., & Sippel, R. S. (2013) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2012.12.002 · Cited by 70 · see citing works
Management of Hypothyroidism During Pregnancy
Montoro, M. N. (1997) · Clinical Obstetrics & Gynecology · doi:10.1097/00003081-199703000-00008 · Cited by 70 · see citing works
Variations in adequate levothyroxine replacement therapy in patients with different causes of hypothyroidism
Gordon, M. B., & Gordon, M. S. (1999) · Endocrine Practice · doi:10.4158/ep.5.5.233 · Cited by 67 · see citing works
Update on Diagnosis of Canine Hypothyroidism
Ferguson, D. C. (1994) · Veterinary Clinics of North America Small Animal Practice · doi:10.1016/s0195-5616(94)50057-3 · Cited by 69 · see citing works
Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations
Woeber, K. A. (2002) · Journal of Endocrinological Investigation · doi:10.1007/bf03343972 · Cited by 67 · see citing works
Pilot study on the assessment of the setpoint of the hypothalamus-pituitary-thyroid axis in healthy volunteers
Benhadi, N., Fliers, E., Visser, T. J., Reitsma, J. B., & Wiersinga, W. M. (2010) · European Journal of Endocrinology · doi:10.1530/eje-09-0655 · Cited by 66 · see citing works
The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross‐over study in thyroidectomized patients
Celi, F. S., Zemskova, M., Linderman, J. D., Babar, N. I., Skarulis, M. C., Csako, G., Wesley, R., Costello, R., Penzak, S. R., & Pucino, F. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03700.x · Cited by 65 · see citing works
The emergence of levothyroxine as a treatment for hypothyroidism
Hennessey, J. V. (2017) · Endocrine · doi:10.1007/s12020-016-1199-8 · Cited by 66 · see citing works
Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient Hypothyroxinemia in Neonates of <28 Weeks' Gestation
Gamma, E. F. L., Leemhuis, A. G., Segura, S. A., GOLOMBEK, S. G., Kok, J. H., Quero, J., Hong, T., Rahbar, M. H., de Escobar, G. M., Fisher, D. A., et al. (2009) · PEDIATRICS · doi:10.1542/peds.2008-2837 · Cited by 64 · see citing works
Monitoring Therapy in Patients Taking Levothyroxine
Helfand, M., & Crapo, L. M. (1990) · Annals of Internal Medicine · doi:10.7326/0003-4819-113-6-450 · Cited by 62 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Thyroid function across the lifespan: do age-related changes matter?
Walsh, J. P. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2022.1463 · Cited by 59 · see citing works
Subclinical Hyperthyroidism: Possible Danger of Overzealous Thyroxine Replacement Therapy
Ross, D. S. (1988) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(12)65409-3 · Cited by 58 · 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
Thyroid Hormone Levels Affected by Time of Blood Sampling in Thyroxine-Treated Patients
AIN, K. B., PUCINO, F., SHIVER, T. M., & BANKS, S. M. (1993) · Thyroid · doi:10.1089/thy.1993.3.81 · Cited by 56 · see citing works
Disorders of the Thyroid Gland
Pellitteri, P. K., Ing, S. W., & Jameson, B. C. (2010) · Elsevier eBooks · doi:10.1016/b978-0-323-05283-2.00124-5 · Cited by 56 · see citing works
The interaction between growth hormone and the thyroid axis in hypopituitary patients: Interaction between growth hormone and thyroid axis
Behan, L. A., Monson, J. P., & Agha, A. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2010.03815.x · Cited by 53 · see citing works
THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?
Wiersinga, W. M. (2017) · European Journal of Endocrinology · doi:10.1530/eje-17-0645 · Cited by 52 · see citing works
Reconciling the Log-Linear and Non–Log-Linear Nature of the TSH-Free T4 Relationship: Intra-Individual Analysis of a Large Population
Rothacker, K. M., Brown, S. J., Hadlow, N. C., Wardrop, R., & Walsh, J. P. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4011 · Cited by 51 · see citing works
A new strategy to estimate levothyroxine requirement after total thyroidectomy for benign thyroid disease
Di Donna, V., Santoro, M. G., de Waure, C., Ricciato, M. P., Paragliola, R. M., Pontecorvi, A., & Corsello, S. M. (2014) · Thyroid · doi:10.1089/thy.2014.0111 · Cited by 52 · see citing works
Can Levothyroxine Be Taken as Evening Dose? Comparative Evaluation of Morning versus Evening Dose of Levothyroxine in Treatment of Hypothyroidism
Rajput, R., Chatterjee, S., & Rajput, M. (2011) · Journal of Thyroid Research · doi:10.4061/2011/505239 · Cited by 52 · see citing works
Free Thyroxine During Early Pregnancy and Risk for Gestational Diabetes
Haddow, J. E., Craig, W. Y., Neveux, L. M., Palomaki, G. E., Lambert-Messerlian, G. M., Malone, F. D., & D’Alton, M. E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149065 · Cited by 51 · see citing works
Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism
Collaborative, N. E. C. H., & Lee, M. M. (1994) · The Journal of Pediatrics · doi:10.1016/s0022-3476(94)70359-0 · Cited by 51 · see citing works
Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy
Hennessey, J. V., & Espaillat, R. (2018) · International Journal of Clinical Practice · doi:10.1111/ijcp.13062 · Cited by 49 · see citing works
Levothyroxine replacement dosage determination after thyroidectomy
Jin, J., Allemang, M. T., & McHenry, C. R. (2013) · The American Journal of Surgery · doi:10.1016/j.amjsurg.2012.10.015 · Cited by 47 · see citing works
Organ-specific effects of tiratricol: a thyroid hormone analog with hepatic, not pituitary, superagonist effects.
Sherman, S., & Ladenson, P. (1992) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jcem.75.3.1517383 · Cited by 47 · see citing works
The log <scp>TSH</scp>–free T4 relationship in a community‐based cohort is nonlinear and is influenced by age, smoking and thyroid peroxidase antibody status
Brown, S. J., Bremner, A. P., Hadlow, N. C., Feddema, P., Leedman, P. J., O'Leary, P. C., & Walsh, J. P. (2016) · Clinical Endocrinology · doi:10.1111/cen.13107 · Cited by 46 · see citing works
Reversible normalisation of serum TSH levels in patients with autoimmune atrophic gastritis who received L-T4 in tablet form after switching to an oral liquid formulation: a case series
Fallahi, P., Ferrari, S. M., Ruffilli, I., & Antonelli, A. (2016) · BMC Gastroenterology · doi:10.1186/s12876-016-0439-y · Cited by 46 · see citing works

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
DOI: 10.1056/nejm198703263161302
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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Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism

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