Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism
Open accessAbstract
A -double-blind crossover trial of a combined preparation of triiodothyronine and thyroxine (1:4 ratio) compared with thyroxine alone was conducted with 99 patients previously stabilized on. thyroxine as treatment for hypothyroidism. Four patients were excluded during the trial and eight afterwards owing to gross deficiencies in taking the tablets. Of the remaining 87 patients 42 (48%) had no -preference for either medication, 29 (33%) preferred thyroxine alone, and 16 (18%) the combination. A high incidence of unpleasant symptoms was experienced during the two months' treatment with the combined preparation. The serum protein-bound iodine levels were lowered (mean reduction 1.8 mug./100 ml.) on the combination, but the labelled T(3)-resin sponge uptake values were not altered and remained in the normal range. on both treatments.
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Earlier studies in the 1960s suggested that LT3 was associated with an excess risk of thyrotoxicosis and its cardiovascular complications.
“Earlier studies in the 1960s suggested that LT3 was associated with an excess risk of thyrotoxicosis and its cardiovascular complications (69).”
From Risk of Death and Adverse Effects in Patients on Liothyronine: A Multisource Systematic Review and Meta-analysis (2025) · cites this paper as [69]
The Results (Table III; page unavailable) report more palpitations and breathlessness during combined LT3/LT4 treatment than during LT4 alone, supporting an excess of cardiovascular symptoms. The paper does not report an excess risk of diagnosed thyrotoxicosis or establish cardiovascular complications of thyrotoxicosis; it also reports a 1970 trial, not a study from the 1960s. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe daily L-T3 dose was administered as a single dose in all trials except four, in which it was divided in two doses.
“The daily L-T3 dose was administered as a single dose in all trials except four, in which it was divided in two doses [37,40,42,43] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [37]
The Dosage passage supports identifying this as a trial in which the daily L-T3 dose was divided rather than given once daily. But patients taking two tablets spaced them 12 hours apart, while those taking three spaced them eight hours apart; the dose was not divided into two administrations for everyone in this trial. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe L-T3 dose administered during combination therapy varied between 5 and 25 g daily, with the exception of the oldest study in which 40-60 g L-T3 was given.
“The L-T3 dose administered during combination therapy varied between 5 and 25 g daily, with the exception of the oldest study in which 40-60 g L-T3 was given [37] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [37]
The earliest study from 1970 and the most recent one from 2009 are not included in the meta-analysis, but all other studies performed between 1999 and 2005 are included.
“The earliest study from 1970 [37] and the most recent one from 2009 [5] are not included in the meta-analysis, but all other studies (performed between 1999 and 2005) are included in the meta-analysis [34] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [37]
The second of these studies involved administration of high doses of thyroid hormones, including doses of T3 of up to 60 mg/day.
“The second of these studies involved administration of high doses of thyroid hormones, including doses of T3 of up to 60 mg/day 52 .”
From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [52]
There were few suggestions of AE consistent with iatrogenic thyrotoxicosis due to overtreatment with T3, and these (biochemical evidence of increased bone resorption or palpitations) arose in studies where the LT4:T3 ratio was particularly low (4:1).
“There were few suggestions of AE consistent with iatrogenic thyrotoxicosis due to over treatment with T3, and these (biochemical evidence of increased bone resorption or palpitations) arose in studies where the LT4:T3 ratio of treatment was particularly low (4:1) 39,52 .”
From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [52]
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Sorted by citations
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“Randomized clinical trials Research into combinations of synthetic LT4 and LT3 began in 1967 (210, 211).”
BackgroundWhy does anyone still use desiccated thyroid USP?
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The emergence of levothyroxine as a treatment for hypothyroidism
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Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism
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“However, in this case, TH replacement doses were higher, 160–240 mcg/day LT4 and 40– 60 mcg/day LT3 (108).”
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“[10,11], complaints of palpitations, irritability, dizziness, tremor, perspiration and shortness of breath have slowed this endeavor.”
BackgroundThyroxine and treatment of hypothyroidism: seven decades of experience
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“On the other hand, studies comparing monotherapy with combined therapy, pointed out that subjects were unable to distinguish treatment and although as many as 18% preferred the combined approach, there was a relatively high incidence of side effects among those using the combination, making the topic more controversia…”
ResultDissatisfaction with thyroxine therapy — could the patients be right?
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“From previous meta-analyses, only two studies reported significant atrial arrhythmias.(17,42) It is important to point out that our study did not titrate LT4 to supraphysiologic levels for which thyrotoxicosis was a concern before starting any combination therapy.”
ResultBiondi, B., Bartalena, L., Chiovato, L., Lenzi, A., Mariotti, S., Pacini, F., Pontecorvi, A., Vitti, P., & Trimarchi, F. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0511-z · Cited by 44 · see citing works
“Hyperthyroid symptoms may increase significantly after L-T3 administration [24], and persistently elevated serum TT3 and FT3 levels may be a risk factor for the development of atrial arrhythmias and progression of acute myocardial ischemia [25, 26].”
BackgroundCombination L-T3 and L-T4 therapy for hypothyroidism
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“[12] examined the responses to T4 therapy alone versus combined with T3 (80 mg T4/20 mg T3) in 87 hypothyroid patients.”
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“These showed no positive results regarding patient preference toward LT4/LT3 therapy and revealed a high incidence of hyperthyroid symptoms (possibly due to excessive doses of LT4/LT3) (10).”
BackgroundResultInfluentialde Carvalho, G. A., Paz-Filho, G., Mesa, C. O., & Graf, H. (2018) · European Journal of Endocrinology · doi:10.1530/eje-17-0947 · Cited by 41 · see citing works
Evaluation of sodium l-thyroxine (T4) requirement in replacement therapy of hypothyroidism
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Time for a reassessment of the treatment of hypothyroidism
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Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality
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“To date, at least 12 randomized controlled trials have examined the effect of combined LT4/LT3 treatment with varying results (9–20).”
Thyroid hormone replacement: current status and challenges
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“0 0 Variable NA No (QOL, M, PP) Appelhof, 2005 [82] 141 100.”
BackgroundRegalbuto, C., Maiorana, R., Alagona, C., Paola, R. D., Cianci, M., Alagona, G., Sapienza, S., Squatrito, S., & PEZZINO, V. (2007) · Thyroid · doi:10.1089/thy.2006.0084 · Cited by 32 · see citing works
“For these reasons after LT4 = LT3 ingestion some patients complain of pal-pitations, irritability, dizziness, and tremor (41).”
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Critical Approach to Hypothyroid Patients With Persistent Symptoms
Biondi, B., Celi, F. S., & McAninch, E. A. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad224 · Cited by 28 · see citing works
The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy
McAninch, E. A., & Bianco, A. C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00446 · Cited by 24 · see citing works
“For example, in studies utilizing doses of LT3 75–100 mcg/day, angina and congestive heart failure were observed (82); in another trial, palpitations, irritability, nervousness, dizziness, tremor, and perspiration were observed on LT4 (80 mcg) plus LT3 (20 mcg) daily (83).”
BackgroundBrigante, G., Santi, D., Boselli, G., Margiotta, G., Corleto, R., Monzani, M. L., Craparo, A., Locaso, M., Sperduti, S., Roy, N., et al. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad172 · Cited by 22 · see citing works
Combination Thyroid Hormone Replacement; Knowns and Unknowns
Taylor, P. N., Eligar, V. S., Muller, I., Scholz, A., Dayan, C. M., & Okosieme, O. E. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00706 · Cited by 21 · see citing works
“It is worth noting that one of the key early studies which favored LT4 monotherapy in terms of patient preference over LT3:LT4 combination treatment (71) used up to 60 mcg of LT3 a day.”
ResultA comparison of thyroxine and desiccated thyroid in patients with primary hypothyroidism
Sawin, C. T., Hershman, J. M., Fernandez-Garcia, R., Ghazvinian, S., Ganda, O. P., & AZUKIZAWA, M. (1978) · Metabolism · doi:10.1016/s0026-0495(78)80024-9 · Cited by 21 · see citing works
Sub-laboratory hypothyroidism and the empirical use of Armour thyroid.
Gaby, A. R. (2004) · PubMed · Cited by 20 · see citing works
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Sawin, C. T. (1985) · Medical Clinics of North America · doi:10.1016/s0025-7125(16)31001-x · Cited by 19 · see citing works
Casula, S., Ettleson, M. D., & Bianco, A. C. (2023) · Endocrine Practice · doi:10.1016/j.eprac.2023.04.003 · Cited by 18 · see citing works
Trends in costs and prescribing for liothyronine and levothyroxine in England and wales 2011–2020
Stedman, M., Taylor, P., Premawardhana, L., Okosieme, O., Dayan, C., & Heald, A. H. (2021) · Clinical Endocrinology · doi:10.1111/cen.14414 · Cited by 16 · see citing works
“However, early studies were small, used somewhat higher doses of liothyronine than used in clinical practice, and resulted in adverse symptoms consistent with thyrotoxicosis.(3) Subsequent more recent trials failed to show convincing benefit for combined thyroid hormone replacement and thus clinical guidelines advise…”
ResultBiondi, B., Pucci, M., Pontieri, G., Formisano, P., & Esposito, R. (2023) · Thyroid · doi:10.1089/thy.2023.0135 · Cited by 15 · see citing works
Heald, A. H., Premawardhana, L., Taylor, P., Okosieme, O., Bangi, T., Devine, H., Livingston, M., Javed, A., Moreno, G. Y. C., Watt, T., et al. (2021) · International Journal of Clinical Practice · doi:10.1111/ijcp.14967 · Cited by 14 · see citing works
Progress Toward and Challenges Remaining for Thyroid Tissue Regeneration
Romitti, M., & Costagliola, S. (2023) · Endocrinology · doi:10.1210/endocr/bqad136 · Cited by 13 · see citing works
Mazzaferri, E. L. (2006) · Yearbook of Medicine · doi:10.1016/s0084-3873(08)70611-4 · Cited by 12 · see citing works
Bahl, S., Taylor, P. N., Premawardhana, L. D., Stedman, M., Heald, A., Dayan, C. M., & Okosieme, O. E. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf449 · Cited by 11 · see citing works
“Earlier studies in the 1960s suggested that LT3 was associated with an excess risk of thyrotoxicosis and its cardiovascular complications (69).”
Latrofa, F., & Pinchera, A. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-517-6_7 · Cited by 11 · see citing works
Mazzaferri, E. L. (2006) · Yearbook of Endocrinology · doi:10.1016/s0084-3741(08)70362-7 · Cited by 10 · see citing works
Triiodothyronine alongside levothyroxine in the management of hypothyroidism?
Gottwald-Hostalek, U., & Kahaly, G. J. (2021) · Current Medical Research and Opinion · doi:10.1080/03007995.2021.1984219 · Cited by 9 · see citing works
Bjerkreim, B. A., Hammerstad, S. S., Gulseth, H. L., Berg, T. J., Lee-Ødegård, S., & Eriksen, E. F. (2022) · Journal of Thyroid Research · doi:10.1155/2022/6423023 · Cited by 8 · see citing works
Liothyronine and levothyroxine prescribing in England: A comprehensive survey and evaluation
Stedman, M., Taylor, P., Premawardhana, L., Okosieme, O., Dayan, C., & Heald, A. H. (2021) · International Journal of Clinical Practice · doi:10.1111/ijcp.14228 · Cited by 8 · see citing works
“Furthermore, early clinical studies used unduly high doses of LT3 that sometimes resulted in unpleasant adverse effects from iatrogenic thyrotoxicosis.(3) Accordingly, existing clinical guidelines do not support the routine use of LT3 in the management of hypothyroidism.”
Combined therapy with levothyroxine and liothyronine for hypothyroidism
Fischman, A., & Domínguez, J. M. (2018) · Medwave · doi:10.5867/medwave.2018.08.7375 · Cited by 7 · see citing works
Gottwald-Hostalek, U., & Tayrouz, Y. (2024) · Current Medical Research and Opinion · doi:10.1080/03007995.2024.2435460 · Cited by 6 · see citing works
“The second of these studies involved administration of high doses of thyroid hormones, including doses of T3 of up to 60 m g/day 52 .”
Therapeutic options in systemic AL amyloidosis.
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Natural desiccated thyroid for the treatment of hypothyroidism?
Heald, A. H., Taylor, P., Premawardhana, L., Stedman, M., & Dayan, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1309159 · Cited by 5 · see citing works
“With its more favorable pharmacokinetics allowing for once daily dosing and clinical trial evidence (9), levothyroxine monotherapy has prevailed as the treatment of choice for primary hypothyroidism.”
BackgroundPresent Trends and Outlook for the Future — Part I
Medvei, V. C. (1982) · Springer eBooks · doi:10.1007/978-94-009-7304-6_22 · Cited by 5 · see citing works
Tratamiento actual del hipotiroidismo: una revisión crítica
Escobar-Morreale, H. F. (2001) · Endocrinología y Nutrición · doi:10.1016/s1575-0922(01)73509-7 · Cited by 5 · see citing works
“Cuando se administraban combina-ciones de T 4 y T 3 , reduciendo sensiblemente la dosis de T 4 administrada, se mantenía el eutiroidismo clínico y se nor-malizaba el PBI plasmático 5,6 .”
BackgroundThyroid function disorders and cardiovascular system
Troshina, E. A., Yukina, M. Y., Ogneva, N. A., & Mazurina, N. V. (2010) · Clinical and experimental thyroidology · doi:10.14341/ket20106112-19 · Cited by 4 · see citing works
“Пять [18, 53, 56, 60, 66] проведенных до этого похожих ис следований также не выявили достоверных преиму ществ комбинированной терапии гипотиреоза.”
Potential uses of T3 in the treatment of human disease
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Medikamentöse Behandlung der chronisch verlaufenden Glomerulonephritiden: Contra
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Les Dysthyroïdies dans le Service de Médecine Interne de l’Hôpital National de Niamey – Niger
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Лечение первичного гипотиреоза: нерешенные вопросы
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Organic medicine. Thyroid hormone replacement therapy, 1891-1977
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Options of Replacement Therapy in Hypothyroidism
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Clinical thyroidology: beyond the 1970s’ TSH-T4 Paradigm
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“Some cited reports of thyrotoxicity with excessive doses of DTE (31) and T4/T3 (32), and the high T3 levels after doses to argue that DTE and T3 should not be prescribed.”
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Psychiatric disorders and thyroid disease
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Pediatric Iatrogenic Movement Disorders
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Peut-on mieux traiter l'hypothyroïdie?
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Cyborg Butterflies, Liminal Medicine: Thyroid Hormone Treatment, 1890-1970
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Study on the TRH test during the course of the treatment of primary hypothyroidism
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Is combination therapy appropriate for hypothyroidism?
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Kant, R., & Verma, V. K. (2018) · Endocrinology & Metabolic Syndrome · doi:10.4172/2161-1017.1000e127
“In some of these studies patients preferred combination LT4/LT3 even though no or minimal statistically significant differences were observed in primary outcomes [6-19].”
BackgroundHesse, V., Lauterbach, H., & Stoll, W. (1977) · Journal of Molecular Medicine · doi:10.1007/bf01490240
“Da eine pr/izise Einstellung mit KombinationsprS_paraten schwierig und uniibersichtlich ist, und zudem Kombinationspr/iparate gegen~ber L-Thyroxin eine h6here Komplikationsrate aufweisen [12], sollte die therapeutische Anwendung von Kombinationsprfiparaten mit relativ hohem T3-Anteil iiberdacht werden und zumindest Pr…”
BackgroundPresent Trends and Outlook for the Future — Part III
Medvei, V. C. (1982) · Springer eBooks · doi:10.1007/978-94-009-7304-6_24
Oyama, T. (1973) · Anästhesiologie und Intensivmedizin · doi:10.1007/978-3-642-65561-6_15
- Authors
- Smith, R. N., Taylor, S. A., & Massey, J. C.
- Affiliations
- Sheffield Children's Hospital (GB)
- ORCID
- Taylor, S. A.
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 1970-10-17
- Volume
- 4
- Issue
- 5728
- Pages
- 145-148
- ISSN
- 0007-1447 (ISSN-L)
- 0959-8138
- 1468-5833
- PMC
- PMC1819870
- OpenAlex
- W2054161925
- Cited by
- 106
- References
- 25
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 7 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 4
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- BMJ (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Abbott Laboratories
- 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, triiodothyronine, thyroxine, drug preference, adverse drug reactions, serum protein-bound iodine, thyroid hormone replacement
- MeSH terms
- Adult, Aged, Clinical Trials as Topic, Drug Synergism, Female, Humans, Hypothyroidism, Male, Middle Aged, Thyroid Function Tests, Thyroxine, Tremor, Triiodothyronine
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