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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
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Abstract

Studies in hypothyroid rats show that, when infused with a combination of thyroxine (T4) plus triiodothyronine (T3) to normalize thyrotropin (TSH), euthyroidism in all organs is only ensured when T(4) and T(3) are administered in a ratio as normally secreted by the rat thyroid. As substitution with T(4)-only results in an abnormal serum T(4)/T(3) ratio, it is also possible that in humans, euthyroidism does not exist at the tissue level in many organs, considering that iodothyronine metabolism in the human and the rat share many similar mechanisms. Recent reports in which cognitive function and well-being are compared in patients with primary hypothyroidism substituted with T(4)-only versus substitution with T(4) plus T(3) result in controversial findings in that either positive or no effects were found. In all these studies T(3) was used in the plain form that results in nonphysiologic serum T(3) peaks. In these studies it is suggested that substitution with T(3 )should preferably be performed with a preparation that slowly releases T(3) to avoid these peaks. In the study reported here we show that treatment of hypothyroid subjects with a combination of T(4) plus slow-release T(3) leads to a considerable improvement of serum T(4) and T(3) values, the T(4)/T(3) ratio and serum TSH as compared to treatment with T(4)- only. Serum T(3) administration with slow-release T(3) did not show serum peaks, in contrast to plain T(3).

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Crossref · 10.1089/105072504323030924

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26 of 26 references verified0 citation errors · 0 not checkable

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  • In clinical trials, slow-release LT3 tablets given to 17 hypothyroid individuals confirmed a slightly slower release of LT3 in the intestine and a less prominent peak T3 in the serum (by approximately 9%) at a later time (from approximately 3.2 to 5 hours).

    “In clinical trials, slow-release LT3 tablets were given to 17 hypothyroid individuals, and the results confirmed a slightly slower release of LT3 in the intestine and a less prominent peak T3 in the serum (by ~9%) at a later time (from ~3.2 to 5 h) (55).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [55]

  • In a recent study, the serum free T4/free T3 ratio was lower during L-T4 + slow-release L-T3 therapy than during L-T4 monotherapy, although still higher than in controls.

    “Proof of principle of such preparations has been obtained in a recent study, in which the serum free T4/free T3 ratio was lower during L-T4 + slow-release L-T3 therapy than during L-T4 monotherapy, although still higher than in controls [76] .”

    From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [76]

  • Hennemann et al's slow-release T3 plus T4 preparation with a T3:T4 ratio of 6:125 showed a delayed and reduced T3 peak time compared with normal combined therapy.

    “With a T3:T4 ratio of 6:125, the preparation showed a delayed and reduced T3 peak time compared with that of normal combined therapy (172).”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [172]

  • The serum TSH level with Hennemann et al's preparation was somewhat higher and broader than that obtained with LT4 monotherapy.

    “The serum TSH level, however, was somewhat higher and broader than that obtained with LT4 monotherapy.”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [172]

  • A sustained-release preparation is not yet available for clinical use.

    “considering that a sustained-release preparation is not yet available for clinical use [80-83]”

    From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [83]

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Authors
Hennemann, G., Docter, R., Visser, T. J., Postema, P. T., & Krenning, E. P.
Affiliations
Erasmus MC (NL)
Venue
Thyroid
Publisher
SAGE Publications
Published
2004-04
Volume
14
Issue
4
Pages
271-275
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/105072504323030924
OpenAlex
W2138756616
Cited by
90
References
25
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 7
FWCI
3.88
Type
journal article
Language
en
Open access
closed
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Thyroid (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
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
primary hypothyroidism, thyroxine, triiodothyronine, T4/T3 ratio, serum TSH, euthyroidism, cognitive function
MeSH terms
Delayed-Action Preparations, Drug Therapy, Combination, Female, Humans, Hypothyroidism, Male, Thyroxine, Triiodothyronine, Cross-Over Studies, Area Under Curve

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