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

Héctor F. Escobar-Morreale, MD, PhD; José I. Botella-Carretero, MD; Manuel Gómez-Bueno, MD; José M. Galán, MD; Vivencio Barrios, MD, PhD; and José Sancho, MD, PhD
[+] Article and Author Information

From Hospital Ramón y Cajal, Madrid, Spain.


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@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.


Ann Intern Med. 2005;142(6):412-424. doi:10.7326/0003-4819-142-6-200503150-00007
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Twenty-eight hypothyroid patients (mean age [±SD], 48 ± 11 years; mean body mass index [±SD], 25.9 ± 7.1 kg/m2) were recruited from October 2000 to January 2003. Twenty healthy women (mean age [±SD], 46 ± 13 years; mean body mass index [±SD], 25.4 ± 5.7 kg/m2) served as the external euthyroid control group. Causes of overt hypothyroidism were chronic lymphocytic thyroiditis in 23 patients and thyroid ablation for Graves disease or toxic multinodular goiter in 5 patients.

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Figures

Grahic Jump Location
Figure 1.
Flow of patients through the study.

T3  = liothyronine (synthetic triiodothyronine); T4  = L-thyroxine (synthetic thyroxine).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Evolution of primary outcomes during the study depending on the sequence of treatment.

Data are means with 95% CIs. Squares indicate the following treatment sequence: 1) L-thyroxine, 75 µg/d, plus liothyronine, 5 µg/d; 2) L-thyroxine, 100 µg/d; 3) L-thyroxine, 87.5 µg/d, plus liothyronine, 7.5 µg/d (  = 14). Circles indicate the following treatment sequence: 1) L-thyroxine, 100 µg/d; 2) L-thyroxine, 75 µg/d, plus liothyronine, 5 µg/d; 3) L-thyroxine, 87.5 µg/d, plus liothyronine, 7.5 µg/d (  = 12). FT3  = free triiodothyronine; FT4  = free thyroxine; TSH = thyroid-stimulating hormone.

Grahic Jump Location

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References

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preference assessment
Posted on March 19, 2005
Stéphane Vinzio
Service de Médecine interne et Nutrition, Hôpital Hautepierre, 67098 Strasbourg, France
Conflict of Interest: None Declared

We read with interest the paper from Escobar-Morreale et al that confirms the lack of practical benefits of combined therapy in hypothyroidism (1). However patients included in the study prefered that combined treatment. The authors suggested that improvements provided by that treatment might be subtle. One other possible explaination is in the way to assess which treatment is prefered. Practcally, it is important that the question wording was about prefered period and not treatment prefered, in order to keep therapy blindness. Moreover it might be interresting to assess preference not only at the end of the study but also at the begining and at the end of each treatement period to confirm the result.

(1)Héctor F. Escobar-Morreale, José I. Botella-Carretero, Manuel Gómez-Bueno, José M. Galán, Vivencio Barrios, and José Sancho. Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing L-Thyroxine plus Liothyronine with L-Thyroxine Alone. Ann Intern Med 2005;142:412-424

Conflict of Interest:

None declared

Hypothyroidism treatment : one hormone or two ?
Posted on April 3, 2005
Jean Eisinger
Centre Hospitalier de Toulon, Var (France)
Conflict of Interest: None Declared

Whereas the hypothyroid patients have been treated during decades with dessicated thyroid extracts, the use of L-thyroxine is nowadays considered as the only therapy for all.

However several studies have demonstrated difference between T4 and T3 effects and triiodothyronine has been used in some heart and muscular conditions. Deiodination abnormalities could be induced by casual events such as selenium deficiency or by chronic disease.

A study published in The New England of Medicine [1] has demonstrated that hypothyroid patients are feeling better with a T4 + T3 association. A new Spanish study seems to support this preference of patients but conclude with "scientific" arguments that "physiologic combinations of L- thyroxine plus liothyronine do not offer any objective advantage over L- thyroxine alone. [2] "

Before this abrupt conclusion on a treatment concerning probably less than 10 % of hypoythyroid patients, it would seem wise to have information on important parameters such as clinical and biological muscular investigations [3] (abnormalities persist several months after the beginning of the thyroxine treatment) or antioxydant status exploration[4], less easy to perform or even to interpratate (increased peroxidations are observed several years after beginning of treatment) [4]. So in spite of some pharmaceutical firms and scientists opinions, T3 prescriptions (with the usual caution, low dosages and appropriate adjustment) cannot be rejected when the clinical improvement is not satisfying with T4.

1.Bunévicius R, Kazanavicius G, Zalinkevicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 340(6):424-429, 1999.

2.Escobar-Morreale HF, Botella-Carretero JI, Gómez-Bueno M, Galán JM, Barrios V, Sancho J. Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing L-Thyroxine plus Liothyronine with L-Thyroxine Alone. Annals of Internal Medicine;142 (6):412-424, 2005.

3.Khaleeli Ali A, Gohil K, McPhail G, Round JM, Edwards RHT. Muscle morphology and metabolism in hypothyroid myopathy : effects of treatments. J Clin Pathol 39:519-526, 1983.

4.Eisinger J, Marie PA, Fontaine G, Calendini C, Ayavou T. Métabolisme énergétique et statut anti-oxydant au cours de myalgies.I- Hypothyroïdie. Lyon Med Med 32 :2167-2170, 1966.

Conflict of Interest:

None declared

Hypothyroidism treatment: as of today, thyroxine alone
Posted on May 5, 2005
Héctor F. Escobar-Morreale
Department of Endocrinology, Hospital Ramón y Cajal, E-28034 Madrid, Spain
Conflict of Interest: None Declared

To the Editor:

We appreciate the opportunity to answer the concerns raised by Dr. Eisinger regarding our recently published study.

We are certainly aware that there are differences in the effects of thyroxine and triiodothyronine. In fact, several studies of our group published in the past have been paramount in understanding that the addition of triiodothyronine to thyroxine is essential to ensure euthyroidism in plasma and all tissues of thyroidectomized rats (1-3).

But thyroid hormone physiology is quite different in humans and in rats. This might contribute to explain why, contrary to the expectations raised by our previous animal data, our study in hypothyroid patients, and most similar studies conducted to date, failed to demonstrate any objective advantage of combined thyroxine plus triiodothyronine replacement therapy over standard treatment with thyroxine alone. And it should be noted that we evaluated clinical and biochemical variables pertaining to most body organs and systems, including the heart.

Yet we agree that it would have been also appropriate to measure markers of skeletal muscle function in our study, even when Dr. Eisinger points-out the evident difficulties inherent to this evaluation. But we are not entirely convinced that, by doing so, we would have found the clues of the preference shown by our patients for combined thyroxine plus triiodothyronine replacement therapy.

On the one hand, our study includes a detailed evaluation of cardiac muscle function, which failed to reveal any benefit of combined thyroxine plus triiodothyronine replacement therapy over thyroxine alone. On the other, the fact that improvement of muscle function may take months after initiation of thyroxine therapy, as correctly highlighted by Dr. Eisinger in his letter, makes unlikely that the preference of our patients for combined thyroxine plus triiodothyronine replacement therapy depended on an improvement of skeletal muscle function, when this treatment was given for only 8 weeks in our study.

Therefore, we do not share Dr. Eisinger's conclusions especially when, to our best knowledge, at present there is no consensus, or even clinical guidelines, about which are the "usual caution, low dosages and appropriate adjustment" for triiodothyronine prescription to hypothyroid patients when "clinical improvement is not satisfying with thyroxine". Moreover, the pharmacokinetic profile of oral triiodothyronine, together with the excessive amount contained in most commercially available preparations, makes its routine use and adjustment particularly difficult.

For the reasons outlined above, and especially considering the possibility of severe adverse events when adding even small doses of triiodothyronine to thyroxine (4), we are obliged to insist in that thyroxine alone should remain the drug of choice for the treatment of hypothyroidism in humans, until clear advantages of combination therapy are demonstrated scientifically.

José I. Botella-Carretero, MD, PhD. Héctor F. Escobar-Morreale, MD, PhD

Department of Endocrinology Hospital Ramón y Cajal, E-28034 Madrid, Spain E-mail: hescobarm.hrc@salud.madrid.org

1. Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995;96:2828-38. 2. Escobar-Morreale HF, Escobar del Rey F, Obregón MJ, Morreale de Escobar G. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996;137:2490-502. 3. Escobar-Morreale HF, Obregón MJ, Hernández A, Escobar del Rey F, Morreale de Escobar G. Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine. Endocrinology. 1997;138:2559-68. 4. Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf). 2004;60:750-7.

Conflict of Interest:

None declared

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Summary for Patients

Comparison of Two Drug Regimens for Hypothyroidism

The summary below is from the full report titled “Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing l-Thyroxine plus Liothyronine with l-Thyroxine Alone.” It is in the 15 March 2005 issue of Annals of Internal Medicine (volume 142, pages 412-424). The authors are H.F. Escobar-Morreale, J.I. Botella-Carretero, M. Gómez-Bueno, J.M. Galán, V. Barrios, and J. Sancho.

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