Serum free triiodothyronine (T3) to free thyroxine (T4) ratio in treated central hypothyroidism compared with primary hypothyroidism and euthyroidism

Sesmilo, Gemma; Simó, Olga; Choque, Lucía; Casamitjana, Roser; Puig-Domingo, Manel; Halperin, Irene

doi:10.1016/S2173-5093(11)70031-9

Article information

Abstract

Bibliography

Download PDF

Statistics

Abstract

The standard treatment of hypothyroidism (central and primary) consists of thyroxine (T4) administration alone. However, the normal thyroid gland produces a small proportion of triiodothyronine (T3) directly into the circulation.

Aim

We aimed to study the free T3 to free T4 ratio in treated central hypothyroidism compared with euthyroidism and treated primary hypothyroidism.

Methods

Eighty-three subjects were included in this cross-sectional study: 36 with central hypothyroidism, 20 with primary hypothyroidism and 27 healthy controls. A clinical history and a physical examination, including height and weight measurement, were performed and body mass index (BMI) was calculated. Fasting blood was drawn to measure T3, T4, free T3, free T4 and TSH.

Results

The free T3 to free T4 ratio was lower in treated central hypothyroidism than in euthyroidism but was similar to treated primary hypothyroidism. Free T4 was higher in treated central and primary hypothyroidism than in euthyroidism. Age, sex and BMI did not affect the free T3 to free T4 ratio.

Conclusions

Treated patients with central hypothyroidism had a lower free T3 to free T4 ratio, similar free T3 levels and higher free T4 concentrations than euthyroid controls, whereas all these parameters were similar in central and primary hypothyroid patients treated with T4. The question of whether these findings translate into adequate tissue concentrations of free thyroid hormones in all tissues remains to be answered. Further studies should aim to determine whether clinical outcomes could be improved by a treatment achieving more physiological plasma concentrations.

Keywords:

Central hypothyroidism

Triiodothyronine to thyroxine ratio

T3

T4

Resumen

El tratamiento habitual del hipotiroidismo (central y primario) consiste en administrar sólo tiroxina (T4). Sin embargo, la glándula tiroides normal produce una proporción pequeña de triyodotironina (T3) que va directamente a la circulación.

Objetivo

Estudiar la razón entre las concentraciones de T3 /T4 circulantes en el hipotiroidismo central tratado respecto al eutiroidismo y al hipotiroidismo primario también tratado.

Métodos

Se incluyeron 83 sujetos en este estudio transversal: 36 presentaban hipotiroidismo central, 20 hipotiroidismo primario y 27 eran controles sanos. Se realizó una historia clínica y una exploración física que incluía la altura y el peso, y se calculó el índice de masa corporal (IMC). Se extrajo sangre en ayunas para medir T3, T4, T3 libre, T4 libre y TSH.

Resultados

La razón T3/T4 circulantes fue inferior en el hipotiroidismo central que en el eutiroidismo, pero similar a la del hipotiroidismo primario. La T4 libre fue mayor en el hipotiroidismo central y en el primario que en el eutiroidismo. La edad, el sexo y el IMC no afectaron la razón T3 /T4 circulante.

Conclusiones

Los pacientes con hipotiroidismo central tratados presentan una razón T3/T4 circulante más baja, niveles de T3 circulante similares y concentraciones de T4 libre superiores a los controles eutiroideos; sin embargo, todos estos parámetros son similares en los pacientes con hipotiroidismo central y primario tratados con T4. No se sabe si esto se traduce en concentraciones tisulares adecuadas de hormonas tiroideas libres en todos los tejidos. Queda por investigar si un tratamiento que obtenga una concentración plasmática más fisiológica sería mejor desde el punto de vista de los resultados clínicos. Es de esperar que se diseñen estudios en esa dirección.

Palabras clave:

Hipotiroidismo central

Razón triyodotironina tiroxina

T3

T4

Full text is only aviable in PDF

References

[1.]

P.R. Larsen, J.E. Silva, M.M. Kaplan.

Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications.

Endocr Rev, 2 (1981), pp. 87-102

[2.]

P.R. Larsen, T.F. Davies, M.-J. Schlumberger, I.D. Hay.

Thyroid physiology and diagnostic evaluation of patients with thyroid disorders.

William's Textbook of Endocrinology, pp. 299-332

[3.]

J. Van Doorn, H.D. van der, F. Roelfsema.

Sources and quantity of 3,5,3’-triiodothyronine in several tissues of the rat.

J Clin Invest, 72 (1983), pp. 1778-1792

http://dx.doi.org/10.1172/JCI111138 | Medline

[4.]

J. Van Doorn, F. Roelfsema, H.D. van der.

Concentrations of thyroxine and 3,5,3’-triiodothyronine at 34 different sites in euthyroid rats as determined by an isotopic equilibrium technique.

Endocrinology, 117 (1985), pp. 1201-1208

http://dx.doi.org/10.1210/endo-117-3-1201 | Medline

[5.]

L.H. Fish, H.L. Schwartz, J. Cavanaugh, M.W. Steffes, J.P. Bantle, J.H. Oppenheimer.

Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans.

N Engl J Med, 316 (1987), pp. 764-770

http://dx.doi.org/10.1056/NEJM198703263161302 | Medline

[6.]

A. Mortoglou, H. Candiloros.

The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy.

Hormones (Athens), 3 (2004), pp. 120-126

[7.]

I.J. Chopra, D.E. Williams, J. Orgiazzi, D.H. Solomon.

Opposite effects of dexamethasone on serum concentrations of 3,3’,5’- triiodothyronine (reverse T3) and 3,3’5-triiodothyronine (T3).

J Clin Endocrinol Metab, 41 (1975), pp. 911-920

http://dx.doi.org/10.1210/jcem-41-5-911 | Medline

[8.]

D.S. Duick, D.W. Warren, J.T. Nicoloff, C.L. Otis, M.S. Croxson.

Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man.

J Clin Endocrinol Metab, 39 (1974), pp. 1151-1154

http://dx.doi.org/10.1210/jcem-39-6-1151 | Medline

[9.]

G.S. Van der, V.M. Darras.

Developmentally defined regulation of thyroid hormone metabolism by glucocorticoids in the rat.

J Endocrinol, 185 (2005), pp. 327-336

http://dx.doi.org/10.1677/joe.1.05974 | Medline

[10.]

G. Sesmilo, B.M. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, et al.

Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial.

J Clin Endocrinol Metab, 86 (2001), pp. 1518-1524

[11.]

E. Ferretti, L. Persani, M.L. Jaffrain-Rea, S. Giambona, G. Tamburrano, P. Beck-Peccoz.

Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.

J Clin Endocrinol Metab, 84 (1999), pp. 924-929

http://dx.doi.org/10.1210/jcem.84.3.5553 | Medline

[12.]

A.S. Bates, B. Bullivant, M.C. Sheppard, P.M. Stewart.

Life expectancy following surgery for pituitary tumours.

Clin Endocrinol (Oxf), 50 (1999), pp. 315-319

[13.]

B. Bulow, L. Hagmar, Z. Mikoczy, C.H. Nordstrom, E.M. Erfurth.

Increased cerebrovascular mortality in patients with hypopituitarism.

Clin Endocrinol (Oxf), 46 (1997), pp. 75-81

[14.]

T.A. Elhadd, T.A. Abdu, R.N. Clayton.

Excess vascular mortality in hypopituitarism: is it the result of estrogen or GH deficiency?.

J Clin Endocrinol Metab, 87 (2002), pp. 3509-3510

http://dx.doi.org/10.1210/jcem.87.7.8586 | Medline

[15.]

J. Lindholm, E.H. Nielsen, P. Bjerre, J.S. Christiansen, C. Hagen, S. Juul, et al.

Hypopituitarism and mortality in pituitary adenoma.

Clin Endocrinol (Oxf), 65 (2006), pp. 51-58

[16.]

T. Rosen, B.A. Bengtsson.

Premature mortality due to cardiovascular disease in hypopituitarism.

Lancet, 336 (1990), pp. 285-288

Medline

[17.]

J.W. Tomlinson, N. Holden, R.K. Hills, K. Wheatley, R.N. Clayton, A.S. Bates, Association between premature mortality and hypopituitarism, et al.

West Midlands Prospective Hypopituitary Study Group.

Lancet, 357 (2001), pp. 425-431

[18.]

J.O. Jorgensen, J. Moller, T. Laursen, H. Orskov, J.S. Christiansen, J. Weeke.

Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults.

Clin Endocrinol (Oxf), 41 (1994), pp. 609-614

[19.]

M.R. Alcântara, R. Salvatori, P.R. Alcântara, L.M. Nóbrega, V.S. Campos, E.C. Oliveira, et al.

Thyroid morphology and function in adults with untreated isolated growth hormone deficiency.

J Clin Endocrinol Metab, 91 (2006), pp. 860-864

http://dx.doi.org/10.1210/jc.2005-2555 | Medline

[20.]

V.V. Fadeyev, T.B. Morgunova, J.P. Sytch, G.A. Melnichenko.

TSH and thyroid hormones concentrations in patients with hypothyroidism receiving replacement therapy with L-thyroxine alone or in combination with L-triiodothyronine.

Hormones (Athens), 4 (2005), pp. 101-107

[21.]

H.F. Escobar-Morreale, F.E. del Rey, M.J. Obregon, G.M. de Escobar.

Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.

Endocrinology, 137 (1996), pp. 2490-2502

http://dx.doi.org/10.1210/endo.137.6.8641203 | Medline

[22.]

M. Slawik, B. Klawitter, E. Meiser, M. Schories, O. Zwermann, K. Borm, et al.

Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine.

J Clin Endocrinol Metab, 92 (2007), pp. 4115-4122

http://dx.doi.org/10.1210/jc.2007-0297 | Medline

[23.]

R. Bunevicius, G. Kazanavicius, R. Zalinkevicius, A.J. Prange Jr..

Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.

N Engl J Med, 340 (1999), pp. 424-429

http://dx.doi.org/10.1056/NEJM199902113400603 | Medline

[24.]

P.W. Clyde, A.E. Harari, E.J. Getka, K.M. Shakir.

Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial.

JAMA, 290 (2003), pp. 2952-2958

http://dx.doi.org/10.1001/jama.290.22.2952 | Medline

[25.]

H.F. Escobar-Morreale, J.I. Botella-Carretero, M. Gomez-Bueno, J.M. Galan, V. Barrios, J. Sancho.

Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.

Ann Intern Med, 142 (2005), pp. 412-424

Medline

[26.]

P. Saravanan, D.J. Simmons, R. Greenwood, T.J. Peters, C.M. Dayan.

Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial.

J Clin Endocrinol Metab, 90 (2005), pp. 805-812

http://dx.doi.org/10.1210/jc.2004-1672 | Medline

[27.]

A.M. Sawka, H.C. Gerstein, M.J. Marriott, G.M. MacQueen, R.T. Joffe.

Does a combination regimen of thyroxine (T4) and 3,5,3’- triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a doubleblind, randomized, controlled trial.

J Clin Endocrinol Metab, 88 (2003), pp. 4551-4555

http://dx.doi.org/10.1210/jc.2003-030139 | Medline

[28.]

W. Siegmund, K. Spieker, A.I. Weike, T. Giessmann, C. Modess, Dabers, 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), 60 (2004), pp. 750-757

[29.]

J.P. Walsh, L. Shiels, E.M. Lim, C.I. Bhagat, L.C. Ward, B.G. Stuckey, et al.

Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism.

J Clin Endocrinol Metab, 88 (2003), pp. 4543-4550

[30.]

O. Alexopoulou, C. Beguin, P. De Nayer, D. Maiter.

Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients.

Eur J Endocrinol, 150 (2004), pp. 1-8

Medline

[31.]

I. Shimon, O. Cohen, A. Lubetsky, D. Olchovsky.

Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism.

Thyroid, 12 (2002), pp. 823-827

http://dx.doi.org/10.1089/105072502760339406 | Medline

[32.]