The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross‐over study in thyroidectomized patients
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Summary: Context The substitution of liothyronine (L‐T3) for levothyroxine (L‐T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L‐T3 for L‐T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L‐T3 and L‐T4. Design Randomized, double‐blind, cross‐over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L‐T3 or L‐T4 with a target TSH ≥ 0·5 ≤ 1·5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed‐over according to the same scheme. Main outcome measures Area under the serum concentration–time curve of TSH from 0 to 60 min (AUC 0–60) and peak TSH serum concentration (Cmax) following thyrotropin‐releasing hormone (TRH) stimulation test, total L‐T4 and L‐T3 dose (mcg/kg), and L‐T4/L‐T3 ratio. Results No difference was observed for time 0 TSH values between L‐T3 and L‐T4 replacement phases (1·48 ± 0·77 vs. 1·21 ± 0·62 mU/l, P = 0·293) at average daily doses of 40·3 ± 11·3 mcg L‐T3 and 115·2 ± 38·5 mcg L‐T4, L‐T3: L‐T4 ratio 0·36 ± 0·06. TRH stimulation test resulted in similar L‐T3 vs. L‐T4 TSH responses with AUC 0–60 of 326·1 (95% CI 232·6–457·1) and 247·1 (95% CI 153·8–397·1) mU* min/l (P = 0·285); and Cmax of 6·83 (95% CI 4·88–9·55) and 5·23 (95% CI 3·31–8·3) mU/l (P = 0·383). Conclusions This is the first study addressing the equivalency between L‐T3 and L‐T4 therapy measured by baseline and TRH‐stimulated TSH. The therapeutic substitution of L‐T3 for L‐T4 was achieved at approximately 1:3 ratio.
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LT3 monotherapy administered three times daily produces stable TSH levels with continued fluctuations in T3 levels, such that they reach the upper end of the normal range with each of the three dose administrations.
“LT3 monotherapy administered three times daily produces stable TSH levels with continued fluctuations in T3 levels, such that they reach the upper end of the normal range with each of the three dose administrations (75,76).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
The Results (Thyroid hormone levels; page unavailable) report similar 24-hour TSH profiles with LT3 and LT4, while T3 levels on LT3 were more variable. The Discussion says mean T3 remained within the normal range throughout 24 hours. Neither passage establishes that T3 reached the upper end of that range after each of the three doses. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome physicians replace part of the usual T4 dose by T3 at a substitution ratio of 3:1 (e.g., 25 μg of T4 replaced by 7.5 μg of T3).
“Some physicians just replace part of the usual T4 dose by T3 at a substitution ratio of 3:1 (e.g., 25 μg of T4 is replaced by 7.5 μg of T3) [80].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [80]
The Results and Discussion report an approximately 1:3 T3:T4 dose equivalence, and the Introduction describes combination therapy as common among practitioners. But the study tested T3 in place of T4, not physicians replacing part of a usual T4 dose at that ratio; it does not give the 25 μg-to-7.5 μg example. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBased on LT3 monotherapy studies, LT3 could be substituted for LT4 at a 1 to 3 ratio, such that 40 μg LT3 was equivalent to 115 μg LT4.
“Based on these LT3 monotherapy studies, it was estimated that in terms of therapeutic equivalence, LT3 could be substituted for LT4 at a 1 to 3 ratio, such that 40 μg LT3 was equivalent to 115 μg LT4 (76).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
LT3 monotherapy administered three times daily is too frequent a dosing regimen for participants to easily adhere to.
“Moreover, as judged by the length of time that it took over the course of the study to reach and maintain the goal TSH, it is too frequent a dosing regimen for participants to easily adhere to.”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
A crossover design is appealing because of the increase in statistical power due to the ability to perform paired analyses.
“A crossover design is appealing because of the increase in statistical power due to the ability to perform paired analyses, as has been performed in prior studies (23,46,50,52,58,59,75,76,107).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
The therapeutic substitution of LT3 for LT4 has previously been calculated to approximate a 1:3 ratio.
“The therapeutic substitution of LT3 for LT4 has previously been calculated to approximate a 1:3 ratio (76).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
The target (TSH 0.5-1.5 mU/l for at least 30 days) was reached by an average daily dose of 40.3 ± 11.3 g L-T3 and 115.2 ± 38.5 g L-T4 (L-T3:L-T4 ratio 0.36 ± 0.06).
“The target (TSH 6 0.5 ^ 1.5 mU/l for at least 30 days) was reached by an average daily dose of 40.3 8 11.3 g L-T3 and 115.2 8 38.5 g L-T4 (L-T3:L-T4 ratio 0.36 8 0.06).”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [71]
Therapeutic substitution of L-T3 for L-T4 was achieved at approximately 1:3 ratio.
“It was concluded that therapeutic substitution of L-T3 for L-T4 was achieved at approximately 1: 3 ratio.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [71]
Ratios of T3 to T4 in combination therapy ranging from 1:3 to 1:17 have been reported.
“Ratios ranging from 1:3 to 1:17 have been reported in several articles (150–153).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [150]
The therapeutic substitution of LT3 for LT4 has previously been calculated to approximate a 1:3 ratio.
“The therapeutic substitution of LT3 for LT4 has previously been calculated to approximate a 1: 3 ratio, as discussed in Topic 5 [76]”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
Based on LT3 monotherapy studies, LT3 could be substituted for LT4 at a 1-3 ratio, such that 40 μg LT3 was equivalent to 115 μg LT4.
“Based on these LT3 monotherapy studies, it was estimated that in terms of therapeutic equivalence, LT3 could be substituted for LT4 at a 1-3 ratio, such that 40 µg LT3 was equivalent to 115 µg LT4 [76].”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
LT3 monotherapy administered three times daily produces stable TSH levels with continued fluctuations in T3 levels, such that T3 reaches the upper end of the normal range with each of the three dose administrations.
“LT3 monotherapy administered three times daily produces stable TSH levels with continued fluctuations in T3 levels, such that they reach the upper end of the normal range with each of the three dose administrations [75, 76].”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [76]
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- Authors
- 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.
- Affiliations
- National Institutes of Health (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Corresponding author
- Celi, Francesco S.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2010-03-25
- Volume
- 72
- Issue
- 5
- Pages
- 709-715
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- PMC
- PMC2888764
- OpenAlex
- W2135039498
- Cited by
- 65
- References
- 32
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 4
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01-DK047057-02, Z01DK047057)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- levothyroxine, liothyronine, thyroid hormone withdrawal, thyroidectomy, thyroid cancer, TRH stimulation test, TSH response, T3/T4 ratio, thyroid hormone replacement, crossover design, dose comparison, TSH receptor mutations
- MeSH terms
- Double-Blind Method, Female, Humans, Hypothyroidism, Male, Metabolic Clearance Rate, Middle Aged, Therapeutic Equivalency, Thyroid Function Tests, Thyroidectomy, Thyrotropin, Thyroxine, Triiodothyronine, Treatment Outcome, Cross-Over Studies, Area Under Curve, Hormone Replacement Therapy
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