Combination L-T3 and L-T4 therapy for hypothyroidism

Wartofsky, Leonard

doi:10.1097/01.med.0000432611.03732.49

Cited by 42Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Combination L-T3 and L-T4 therapy for hypothyroidism

Wartofsky, Leonard·2013·Current Opinion in Endocrinology, Diabetes & Obesity

DOI 10.1097/01.med.0000432611.03732.49

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Abstract

PURPOSE OF REVIEW: Because of the longstanding controversy regarding whether hypothyroid patients can be optimally replaced by treatment with levothyroxine (L-T4) alone, numerous studies have addressed potential benefits of combined therapy of triiodothyronine (T3) with L-T4. Results of these studies have failed to support a potential benefit of combined therapy. A strong argument for the addition of L-T3 to L-T4 monotherapy has been lacking until recent genetic studies indicated a rationale for such therapy among a small fraction of the hypothyroid patient population. RECENT FINDINGS: Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid state and the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormone concentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associated with reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroid-pituitary feedback, and in responses to thyroid hormone treatment. SUMMARY: Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients. Future well controlled clinical trials will be required to more fully resolve the controversy.

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Genetic variations in thyroid hormone transport and metabolism might make certain individuals more responsive to T3 supplementation.
“Genetic variations in thyroid hormone transport and metabolism, such as those involving deiodinase enzymes, might make certain individuals more responsive to T3 supplementation, particularly those with specific genetic polymorphisms affecting the conversion of T4 to T3 [30].”
From Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis (2024) · cites this paper as [30]
In the physiological state, the normal ratio of T4:T3 released by the thyroid is approximately 14:1.
“Of note, in the physiological state, the normal ratio of T4:T3 released by the thyroid is approximately 14:1 (39).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [39]
The normal thyroid gland releases T4 and T3 in a ratio of about 14:1.
“The normal release ratio of T4:T3 by the thyroid gland is approximately 14:1.24”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [24]

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Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study
Bjerkreim, B. A., Hammerstad, S. S., Gulseth, H. L., Berg, T. J., Omdal, L. J., Lee-Ødegård, S., & Eriksen, E. F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.816566 · Cited by 24 · see citing works
“There were no differences in blood pressure or resting heart rate between the two treatment groups. n.org February 2022 | Volume 13 | Article 8165661 Frontiers in Endocrinology | www.frontiersi TSH in patients on LT3 was slightly higher (median 1.33 mU/L (interquartile range (IQR) 0.47-2.26)) than in patients on LT4 (…”
BackgroundInfluential
Is measurement of TT3 by immunoassay reliable at low concentrations? A comparison of the Roche Cobas 6000 vs. LC–MSMS
Masika, L. S., Zhao, Z., & Soldin, S. J. (2016) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2016.02.004 · Cited by 23 · see citing works
“Wartofsky states “Perhaps 20% of hypothyroid patients treated with T4 alone continue to complain of symptoms suggesting thyroid hormone deficiency”[3].”
BackgroundInfluential
Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives?
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018) · Journal of Thyroid Research · doi:10.1155/2018/3239197 · Cited by 20 · see citing works
Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism
Park, E., Jung, J., Araki, O., Tsunekawa, K., Park, S. Y., Kim, J., Murakami, M., Jeong, S., & Lee, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-28480-0 · Cited by 18 · see citing works
Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum
Banne, E., Meiner, V., Shaag, A., Katz‐Brull, R., Gamliel, A., Korman, S. H., Cederboim, S. H., Duvdevani, M. P., Frumkin, A., Zilkha, A., et al. (2015) · JIMD Reports · doi:10.1007/8904_2015_474 · Cited by 18 · see citing works
“Triiodothyronine in treating infantile hypothyroidism is rarely needed (Wartofsky 2013) and can probably be explained by disrupted pentose phosphate pathway, known to be important for thyroid function (Wartofsky 2013).”
Background
Diagnosis and Management of Iatrogenic Hypothyroidism
Peterson, M. E. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-22652-3.00023-2 · Cited by 15 · see citing works
Refractory hypothyroidism: unraveling the complexities of diagnosis and management
Quiroz-Aldave, J. E., Concepción-Zavaleta, M. J., Durand-Vásquez, M. D. C., Concepción-Urteaga, L. A., Gamarra-Osorio, E. R., Suárez-Rojas, J., Rafael-Robles, L. D. P., Paz-Ibarra, J., & Román-González, A. (2023) · Endocrine Practice · doi:10.1016/j.eprac.2023.09.003 · Cited by 14 · see citing works
Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis
Nassar, M., Hassan, A., Ramadan, S., Desouki, M. T., Hassan, M. A., & Chaudhuri, A. (2024) · BMC Endocrine Disorders · doi:10.1186/s12902-024-01612-6 · Cited by 12 · see citing works
“Genetic variations in thyroid hormone transport and metabolism, such as those involving deiodinase enzymes, might make certain individuals more responsive to T3 supplementation, particularly those with specific genetic polymorphisms affecting the conversion of T4 to T3 [30].”
Background
Determinants and mediating mechanisms of quality of life and disease-specific symptoms among thyroid cancer patients: the design of the WaTCh study
Mols, F., Schoormans, D., Netea-Maier, R. T., Husson, O., Beijer, S., Deun, K. V., Zandee, W. T., Kars, M., Poppel, P. W., Şimşek, S., et al. (2023) · Thyroid Research · doi:10.1186/s13044-023-00165-5 · Cited by 10 · see citing works
LT4/LT3 Combination Therapy vs. Monotherapy with LT4 for Persistent Symptoms of Hypothyroidism: A Systematic Review
Vargas‐Uricoechea, H., & Wartofsky, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179218 · Cited by 11 · see citing works
“…the effectiveness of monotherapy with LT4 in relation to the normalization of TSH and T4 levels, a significant proportion of patients with ostensibly “normal” TSH levels experience persistent symptoms compatible with hypothyroidism, such as fatigue, weight gain, and “brain fog” [11,12].”
Background
Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study
Bjerkreim, B. A., Hammerstad, S. S., Gulseth, H. L., Berg, T. J., Lee-Ødegård, S., Rangberg, A., Jonassen, C. M., Budge, H., Morris, D. E., Law, J., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.785175 · Cited by 9 · see citing works
“Further, it is still controversial whether these patients experience alleviation of symptoms when switching to a combination therapy with levothyroxine (LT4) and liothyronine (LT3) (9).”
Background
The Relationship between Gastrointestinal Health, Micronutrient Concentrations, and Autoimmunity: A Focus on the Thyroid
Ruscio, M., Guard, G., Piedrahita, G., & D’Adamo, C. R. (2022) · Nutrients · doi:10.3390/nu14173572 · Cited by 10 · see citing works
Association of DIO2 and MCT10 Polymorphisms With Persistent Symptoms in LT4-Treated Patients in the UK Biobank
Jensen, C. Z., Isaksen, J. L., Ahlberg, G., OLESEN, M. S., Nygaard, B., Ellervik, C., & Kanters, J. K. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad556 · Cited by 6 · see citing works
Drug delivery systems for thyroid disease treatment: A mini review on current therapies and alternative approaches
Kerrigan, L., Stewart, S. A., Domínguez‐Robles, J., Brady, A. J., Ammar, A. A., Donnelly, R. F., Permana, A. D., & Larrañeta, E. (2023) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2023.104861 · Cited by 7 · see citing works
“Therefore, around 80% of daily T3 comes from the conversion of T4 into T3 via-deiodination catalysed by iodothyronine deiodinases [7,8] (Figure 1B), the main difference between T3 and T4 being the number of iodine groups.”
Background
The effect of four-week levothyroxine treatment on hormonal regulation of adenylyl cyclase in the brain and peripheral tissues of obese rats
Derkach, K. V., Kuznetsova, L. A., Chistyakova, O. V., Игнатьева, П. А., & Shpakov, A. O. (2015) · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology · doi:10.1134/s1990747815040030 · Cited by 4 · see citing works
“Thus, the T4 and T3 replacement therapy can be considered as one of the promising approaches to correcting obe sity, MS and DM2 [4], as was confirmed by our results.”
BackgroundResult
There is no ‘universal fit’: Reflections on the use of l-triiodothyronine in the treatment of hypothyroidism
Duntas, L. H., & Wartofsky, L. (2015) · Metabolism · doi:10.1016/j.metabol.2015.11.005 · Cited by 3 · see citing works
“Although the study was considered underpowered [15], the presence of Thr92Ala was linked to reduced T4 to T3 conversion in patients on monotherapy, and its presence signaled a potentially better response to T4/T3 treatment [15,16].”
Background
Liothyronine use in primary hypothyroidism — current concepts
Concepción‐Zavaleta, M. J., Ildefonso-Najarro, S. P., Paz‐Ibarra, J., Fernández-Dávila, F. V., Condori, D. C. D.-G., Rivera-Fabián, K., Herrera-Cabezas, R. G., & Urteaga, L. A. C. (2021) · Endokrynologia Polska · doi:10.5603/ep.a2021.0093 · Cited by 2 · see citing works
“Recent genetic studies have shown the importance of deiodinases in maintaining the euthyroid state, as well as the growing evidence of polymorphisms of these, which would affect the conversion of T4 to T3 [7], providing a solid argument for the addition of LT3 to the therapy.”
It’s Not Lupus This Time! A Case of Worsening Hypothyroidism in a Patient With Nephrotic Syndrome
Iqbal, S., Wan, W. Y., & Mitchell, N. E. (2022) · Cureus · doi:10.7759/cureus.25355 · Cited by 2 · see citing works
“Some experts have suggested adding liothyronine in patients who have an insufficient clinical response to levothyroxine alone; however, this combination has not been proven in efficacy in large clinical trials as of yet [8].”
Background
T3 therapy in hypothyroidism. Still more questions than answers
Concepción‐Zavaleta, M. J., Arroyo, J., Zavaleta‐Gutiérrez, F. E., & Urteaga, L. A. C. (2021) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000378 · Cited by 2 · see citing works
“No guidelines have recommended thyroid hormone replacement with L-T3 alone, but the question remains whether L-T3 + L-T4 combination therapy may be better than levothyroxine alone in a selected group of patients with hypothyroidism (2).”
Background
Process Development and Scale-up of T3-Sulfate, A New Prodrug Alternative to the Conventional Hormone Therapy of Hypothyroidism
Lattuada, L., Argese, M., Boi, V., Galimberti, L., & Gazzetto, S. (2014) · Organic Process Research & Development · doi:10.1021/op500222p · Cited by 1 · see citing works
¿Es necesaria la medición de la T3 para el diagnóstico de hipotiroidismo primario?
Barrera, C. A. B. (2017) · Revista Colombiana de Endocrinología Diabetes & Metabolismo · doi:10.53853/encr.2.3.91 · Cited by 1 · see citing works
New aspects of an old dilemma: treatment of hypothyroidism with L-thyroxine combined with L-triiodothyronine
Duntas, L. H. (2017) · Clinical and experimental thyroidology · doi:10.14341/ket2017314-19 · Cited by 1 · see citing works
“Thus, combination treatment of LT4+LT3 represented an endeavor to concurrently achieve clinical and biochemical euthyroidism [14].”
Background
Thyroid Hormone Therapy and Thyrotropin Suppression
Wartofsky, L. (2016) · Springer eBooks · doi:10.1007/978-1-4939-3314-3_36
Terapia de suplencia tiroidea: una historia del siglo XIX que aún genera noticias en el siglo XXI
Roca, A. J. (2018) · Revista Colombiana de Endocrinología Diabetes & Metabolismo · doi:10.53853/encr.5.1.340
Decreased sensitivity of thyrotropin-thyroid hormone feedback control in hypothyroid and athyreotic patients treated with levothyroxine. Is serum triiodothyronine involved?
Solter, D., & Solter, M. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2017.11.003
Thermal Inkjet Printing of Combination Synthetic LT 3 +LT 4 May Be a Novel Method for Personalizing the Treatment of Hypothyroidism in the Future
Leung, A. M. (2018) · Clinical Thyroidology · doi:10.1089/ct.2018;30.468-470
Symptoms Strongly Drive the Consideration of Alternative Thyroid Hormone–Replacement Options in Patients with Hypothyroidism
Leung, A. M. (2018) · Clinical Thyroidology · doi:10.1089/ct.2018;30.523-525
Prevalence of a Iodothyronine Deiodinase 2 gene single nucleotide polymorphism in children with congenital hypothyroidism from Western Romania and impact on TSH levels
Mang, N., Tămaş, L., Mărginean, O., Marian, C., Ursoniu, S., & Anghel, A. (2019) · Revista română de medicină de laborator · doi:10.2478/rrlm-2019-0012
Correlation of Residual Symptoms With Triiodothyronine (T3) in Patients Treated for Hypothyroidism
Naushad, A. A., Chirag, L. U., Nikitha, S., Sourabh, S., Kolla, B., Selvan, C., Kalra, P., Manjunath, P., & Ganavi, Y. P. (2025) · Cureus · doi:10.7759/cureus.78095
“On the other hand, patients do report a better quality of life when on the combination therapy [8].”
Combination therapy with levothyroxine and liothyronine in hypothyroid patients with persistent symptoms: A case series
Peterman, K., Tacata, R. H. N., Cerezo, N., & Casimiro, I. (2025) · Journal of Clinical and Translational Endocrinology Case Reports · doi:10.1016/j.jecr.2025.100201
Additional file 1 of Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis
Nassar, M., Hassan, A., Ramadan, S., Desouki, M., Hassan, M. A., & Chaudhuri, A. (2024) · Figshare · doi:10.6084/m9.figshare.26733783

Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?
Wiersinga, W. M. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0879 · Cited by 43 · see citing works
Does Combination T4 And T3 Therapy Make Sense?
McDermott, M. T. (2012) · Endocrine Practice · doi:10.4158/ep12076.ra · Cited by 15 · 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
Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?
Porcelli, T., & Salvatore, D. (2020) · Endocrine · doi:10.1007/s12020-020-02391-5 · Cited by 3 · see citing works
For Some, l-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale
Kim, B. W., & Bianco, A. C. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0410 · Cited by 18 · see citing works

Authors: Wartofsky, L.
Affiliations: Georgetown University (US)
Corresponding author: Wartofsky, Leonard
ORCID: Wartofsky, Leonard
Venue: Current Opinion in Endocrinology, Diabetes & Obesity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2013-10
Volume: 20
Issue: 5
Pages: 460-466
ISSN: 1752-296X (ISSN-L)
DOI: 10.1097/01.med.0000432611.03732.49
OpenAlex: W2110647490
Cited by: 42
References: 55
Citations by year: 2025: 2 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 4 · 2019: 1 · 2018: 9 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 4
FWCI: 0.59
Type: journal article
Language: en
Open access: closed
Locations: Current Opinion in Endocrinology Diabetes and Obesity (publishedVersion)
PubMed (publishedVersion)
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: hypothyroidism, levothyroxine, triiodothyronine, type 2 deiodinase, T4 to T3 conversion, thyroid hormone replacement, fatigue, obesity
MeSH terms: Chemistry, Pharmaceutical, Drug Combinations, Humans, Hypothyroidism, Iodide Peroxidase, Polymorphism, Genetic, Thyroxine, Triiodothyronine

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Combination L-T3 and L-T4 therapy for hypothyroidism

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