Thyroid hormone replacement has been used for more than 100 years in the treatment of hypothyroidism, and there is no doubt about its overall efficacy. Desiccated thyroid contains both thyroxine (T4) and triiodothyronine (T3); serum T3 frequently rises to supranormal values in the absorption phase, associated with palpitations. Liothyronine (T3) has the same drawback and requires twice-daily administration in view of its short half-life. Synthetic levothyroxine (L-T4) has many advantages: in view of its long half-life, once-daily administration suffices, the occasional missing of a tablet causes no harm, and the extrathyroidal conversion of T4 into T3 (normally providing 80% of the daily T3 production rate) remains fully operative, which may have some protective value during illness. Consequently, L-T4 is nowadays preferred, and its long-term use is not associated with excess mortality. The mean T4 dose required to normalize serum thyroid stimulating hormone (TSH) is 1.6 µg/kg per day, giving rise to serum free T4 (fT4) concentrations that are slightly elevated or in the upper half of the normal reference range. The higher fT4 values are probably due to the need to generate from T4 the 20% of the daily T3 production rate that otherwise is derived from the thyroid gland itself. The daily maintenance dose of T4 varies widely between 75 and 250 µg. Assessment of the appropriate T4 dose is by assay of TSH and fT4, preferably in a blood sample taken before ingestion of the subsequent T4 tablet. Dose adjustments can be necessary in pregnancy and when medications are used that are known to interfere with the absorption or metabolism of T4. A new equilibrium is reached after approximately 6 weeks, implying that laboratory tests should not be done earlier. With a stable maintenance dose, an annual check-up usually suffices. Accumulated experience with L-T4 replacement has identified some areas of concern. First, the bioequivalence sometimes differs among generics and brand names. Second, many patients on T4 replacement have a subnormal TSH. TSH values of ≤0.1 mU/l carry a risk of development of atrial fibrillation and are associated with bone loss although not with a higher fracture rate. It is thus advisable not to allow TSH to fall below – arbitrarily – 0.2 mU/l. Third, recent animal experiments indicate that only the combination of T4 and T3 replacement, and not T4 alone, ensures euthyroidism in all tissues of thyroidectomized rats. It is indeed the experience of many physicians that there exists a small subset of hypothyroid patients who, despite biochemical euthyroidism, continue to complain of tiredness, lack of energy, discrete cognitive disorders and mood disturbances. As organs vary in the extent to which their T3 content is derived from serum T3 or locally produced T3 from T4, these complaints may have a biologic substrate; for example, brain T3 content is largely determined by local deiodinase type II activity. Against this background it is of interest that a number of psychometric scores improved significantly in hypothyroid patients upon substitution of 50 µg of their T4 replacement dose by 12.5 µg T3. Confirmatory studies on this issue are urgently awaited. It could well be that a slow-release preparation containing both T4 and T3 might improve the quality of life, compared with T4 replacement alone, in some hypothyroid patients.

1.
Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990;258:E715–E726.
[PubMed]
2.
Escobar-Morreale HF, Escobar del Rey F, Obregon MJ, Morreale de Escobar G: Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996;137:2490–2502.
[PubMed]
3.
Rees-Jones RW, Larsen PR: Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism 1977;26:1213–1218.
[PubMed]
4.
Le Boff MS, Kaplan MM, Silva JE, Larsen PR: Bioavailability of thyroid hormones from oral replacement preparations. Metabolism 1982;31:900–905.
[PubMed]
5.
MacGregor AG: Why does anybody use thyroid B.P.? Lancet 1961;i:329–332.
6.
Jackson IMD, Cobb WE: Why does anyone still use desiccated thyroid U.S.P.? Am J Med 1978;64:284–288.
[PubMed]
7.
Smith RN, Taylor SA, Massey JC: Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Lancet 1970;iv:145–148.
8.
Kaufman SC, Gross TP, Kennedy DL: Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1991:1:285–291.
[PubMed]
9.
Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G, Greenspan FS, McDougall IR, Nikolai TF: Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. J Am Med Assoc 1995;273(10):808–812.
10.
Vanderpump MPJ, Ahlquist JAO, Franklyn JA, Clayton RN: Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br Med J 1996;313:539–544.
11.
Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH: Replacement dose, metabolism and bioavailability of levothyroxine in the treatment of hypothyroidism. N Engl J Med 1987;316:764–770.
[PubMed]
12.
Kabadi UM: Optimal daily levothyroxine dose in primary hypothyroidism. Its relation to pretreatment thyroid hormone indexes. Arch Intern Med 1989;149:2209–2212.
[PubMed]
13.
Kabadi UM, Jackson T: Serum thyrotropin in primary hypothyroidism. A possible predictor of optimal daily levothyroxine dose in primary hypothyroidism. Arch Intern Med 1995;155:1046–1048.
[PubMed]
14.
Roti E, Minelli R, Gardini E, Braverman LE: The use and misuse of thyroid hormone. Endocr Rev 1993;14:401–423.
[PubMed]
15.
Mandel SJ, Brent GA, Larsen PR: Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993;119:492–502.
[PubMed]
16.
Toft AD: Thyroxine therapy. N Engl J Med 1994;331:174–180.
[PubMed]
17.
Oppenheimer JH, Braverman LE, Toft A, Jackson IM, Ladenson PW: Thyroid hormone treatment: when and what? J Clin Endocrinol Metab 1995;80:2873–2883.
[PubMed]
18.
Lindsay RS, Toft AD: Hypothyroidism. Lancet 1997;349:413–416.
[PubMed]
19.
Helfland M, Capro LM: Monitoring therapy in patients taking levothyroxine. Ann Intern Med 1990;113:450–454.
[PubMed]
20.
Symons RG, Murphy LJ: Acute changes in thyroid function tests following ingestion of thyroxine. Clin Endocrinol 1983;19:539–546.
21.
Ain KB, Pucino F, Shiver TM, Banks SM: Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients. Thyroid 1993;3:81–85.
[PubMed]
22.
Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001;344:1743–1749.
[PubMed]
23.
Utiger RD: Estrogen, thyroxine binding in serum, and thyroxine therapy. N Engl J Med 2001;344:1784–1785.
[PubMed]
24.
Kaplan MM: Monitoring thyroxine treatment during pregnancy. Thyroid 1992;2:147–152.
[PubMed]
25.
Sawin CT, Herman T, Molitch ME, London MH, Kramer SM: Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;75:206–209.
[PubMed]
26.
Cunningham JJ, Barzel US: Lean body mass is a predictor of the daily requirement of thyroid hormone in older men and women. J Am Geriatric Soc 1984;32:204–207.
[PubMed]
27.
Olveira G, Almaraz MC, Soriguer F, Garriga MJ, Gonzalez-Romero S, Tinahones F, Ruiz de Adana MS: Altered bioavailability due to changes in the formulation of a commercial preparation of levothyroxine in patients with differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 1997;46(6):707–711.
28.
Dong BJ, Hauck WW, Gambertoglio JG, Gee L, White JR, Bubp JL, Greenspan FS: Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. J Am Med Assoc 1997;277(15):1205–1213.
29.
Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, Tamburrano G, Beck-Peccoz P: Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999;84:924–929.
[PubMed]
30.
Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC: Thyroxine prescription in the community: serum thyroid stimulating hormone assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993;43:107–109.
[PubMed]
31.
Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY: Effect on bone mass of long-term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996;81:4278–4289.
[PubMed]
32.
Leese GP, Jung RT, Guthrie C, Waugh N, Browning MCK: Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH. Clin Endocrinol 1992;37:500–503.
33.
Solomon BL, Wartofsky L, Burman KD: Prevalence of fractures in postmenopausal women with thyroid disease. Thyroid 1993;3:17–23.
[PubMed]
34.
Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D’Agostino RB: Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331(19):1249–1252.
35.
Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, Saccà L, Bellastella A, Lombardi G: Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77(2):334–338.
36.
Mercuro G, Panzuto MG, Bina A, Leo M, Cabula R, Petrini L, Pigliaru F, Mariotti S: Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J Clin Endocrinol Metab 2000;85(1):159–164.
37.
Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Saccà L, Filetti S, Lombardi G, Perticone F: Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000;85(12):4701–4705.
38.
Shapiro LE, Sievert R, Ong L, Ocampo EL, Chance RA, Lee M, Nanna M, Ferrick K, Surks MI: Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of L-thyroxine. J Clin Endocrinol Metab 1997;82(8):2592–2595.
39.
Peterson K, Bengtsson C, Lapidus L, Lindstedt G, Nyström E: Morbidity, mortality and quality of life for patients treated with levothyroxine. Arch Intern Med 1990;150:2077–2081.
[PubMed]
40.
Escobar-Morreale HF, Obregon 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;96:2828–2838.
[PubMed]
41.
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424–429.
[PubMed]
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