Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing l-Thyroxine plus Liothyronine with l-Thyroxine Alone

  1. Héctor F. Escobar-Morreale, MD, PhD;
  2. José I. Botella-Carretero, MD;
  3. Manuel Gómez-Bueno, MD;
  4. José M. Galán, MD;
  5. Vivencio Barrios, MD, PhD; and
  6. José Sancho, MD, PhD
  1. From Hospital Ramón y Cajal, Madrid, Spain.

    Abstract

    Background: Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results.

    Objective: To evaluate combinations of l-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland.

    Design: Randomized, double-blind, crossover trial.

    Setting: Academic research hospital.

    Participants: 28 women with overt primary hypothyroidism.

    Intervention: Crossover trial comparing treatment with l-thyroxine, 100 µg/d (standard treatment), versus treatment with l-thyroxine, 75 µg/d, plus liothyronine, 5 µg/d (combination treatment), for 8-week periods. All patients also received l-thyroxine, 87.5 µg/d, plus liothyronine, 7.5 µg/d (add-on combination treatment), for a final 8-week add-on period.

    Measurements: Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes.

    Results: Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015).

    Limitations: Treatment with l-thyroxine, 87.5 µg/d, plus liothyronine, 7.5 µg/d, was an add-on regimen and was not randomized.

    Conclusions: Physiologic combinations of l-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

    Article and Author Information

    • Note: An earlier version of this paper was presented at the Endocrine Society's 85th Annual Meeting in Philadelphia, Pennsylvania, 19–22 June 2003.

    • Acknowledgments: The authors thank Genoveva González for excellent technical help; Robertas Bunevicius and Carlos Peiró for invaluable advice regarding the tests of quality of life, mood, and psychometric functionality; and Ana Tabuenca for help with power analysis.

    • Grant Support: By Merck KgaA, Darmstad, Germany. Dr. Botella-Carretero is supported by fellowships from the Consejería de Educación, Comunidad de Madrid (01/0430/01) and from the Fondo de Investigación Sanitaria (01/F072), Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain.

    • Potential Financial Conflicts of Interest: Grants received: H.F. Escobar-Morreale (Merck KgaA, Darmstad, Germany).

    • Requests for Single Reprints: Héctor F. Escobar-Morreale, MD, PhD, Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar Km 9'1, E-28034 Madrid, Spain; e-mail, hescobarm.hrc{at}salud.madrid.org.

    • Current Author Addresses: Drs. Escobar-Morreale, Botella-Carretero, and Sancho: Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar Km 9'1, E-28034 Madrid, Spain.

    • Drs. Gómez-Bueno and Barrios: Department of Cardiology, Hospital Ramón y Cajal, Carretera de Colmenar Km 9'1, E-28034 Madrid, Spain.

    • Dr. Galán: Department of Neurophysiology, Hospital Ramón y Cajal, Carretera de Colmenar Km 9'1, E-28034 Madrid, Spain.

    • Author Contributions: Conception and design: H.F. Escobar-Morreale.

    • Analysis and interpretation of the data: H.F. Escobar-Morreale, J.I. Botella-Carretero, V. Barrios.

    • Drafting of the article: H.F. Escobar-Morreale, J.I. Botella-Carretero, M. Gómez-Bueno, J. Gálan, V. Barrios, J. Sancho.

    • Critical revision of the article for important intellectual content: H.F. Escobar-Morreale, J. Sancho.

    • Final approval of the article: H.F. Escobar-Morreale, J.I. Botella-Carretero, M. Gómez-Bueno, J. Gálan, V. Barrios, J. Sancho.

    • Provision of study materials or patients: H.F. Escobar-Morreale, J.I. Botella-Carretero, M. Gómez-Bueno, J. Gálan.

    • Statistical expertise: H.F. Escobar-Morreale, J.I. Botella-Carretero.

    • Obtaining of funding: H.F. Escobar-Morreale.

    • Administrative, technical, or logistic support: H.F. Escobar-Morreale, J. Sancho.

    • Collection and assembly of data: J.I. Botella-Carretero.

    Responses to this article

    • Hypothyroidism treatment: as of today, thyroxine alone
      • Héctor F. Escobar-Morreale and
      • José I. Botella-Carretero
      Ann Intern Med published online October 26, 2009
    • Hypothyroidism treatment : one hormone or two ?
      • Jean Eisinger
      Ann Intern Med published online October 26, 2009
    • preference assessment
      • Stéphane Vinzio and
      • Bernard Goichot
      Ann Intern Med published online October 26, 2009

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    1. Ann Intern Med March 15, 2005 vol. 142 no. 6 412-424
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