Rodriguez-Gutierrez R, Maraka S, Ospina NS, Montori VM, Brito JP. Levothyroxine overuse: time for an about face? Lancet Diabetes Endocrinol. 2016;5(4):246–8.
Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, Hamilton W, Okosieme O, Panicker V, Thomas SL, et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med. 2014;174(1):32–9.
Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-being in patients on ‘adequate’ doses of l-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol. 2002;57(5):577–85.
Engum A, Bjøro T, Mykletun A, Dahl AA. An association between depression, anxiety and thyroid function--a clinical fact or an artefact? Acta Psychiatr Scand. 2002;106(1):27–34.
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–751.
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.
Braverman LE, Vagenakis A, Downs P, Foster AE, Sterling K, Ingbar SH. Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man. J Clin Invest. 1973;52(5):1010–7.
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 Phys. 1990;258(4 Pt 1):E715–26.
van de Ven AC, Netea-Maier RT, de Vegt F, Ross HA, Sweep FC, Kiemeney LA, Hermus AR, den Heijer M. Is there a relationship between fatigue perception and the serum levels of thyrotropin and free thyroxine in euthyroid subjects? Thyroid. 2012;22(12):1236–43.
Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JG, Wiersinga WM. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol. 2005;153(6):747–53.
Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008;299(7):769–77.
Woeber KA. Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations. J Endocrinol Investig. 2002;25(2):106–9.
Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011;6(8):e22552.
Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA. TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wien Klin Wochenschr. 2005;117(18):636–40.
Ito M, Miyauchi A, Morita S, Kudo T, Nishihara E, Kihara M, Takamura Y, Ito Y, Kobayashi K, Miya A, et al. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. 2012;167(3):373–8.
Peterson SJ, McAninch EA, Bianco AC. Is a normal TSH synonymous with “Euthyroidism” in levothyroxine monotherapy? J Clin Endocrinol Metab. 2016;101(12):4964–73.
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(6):2828–38.
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(6):424–9.
Bunevicius R, Jakuboniene N, Jakubonien N, Jurkevicius R, Cernicat J, Lasas L, Prange AJ. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine. 2002;18(2):129–33.
Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. 2003;290(22):2952–8.
Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. 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 double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551–5.
Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005;11(4):223–33.
Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ. 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. 2003;88(10):4543–50.
Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, van Weert HC, Wiersinga WM. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666–74.
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. Ann Intern Med. 2005;142(6):412–24.
Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. 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. 2005;90(2):805–12.
Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, Kirsch G, Sänger E, Engel G, Hamm AO, 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. 2004;60(6):750–7.
Nygaard B, Jensen EW, Kvetny J, Jarløv A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895–902.
Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, Momtazi S, Musavinasab N, Hayatbakhsh MR. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80–9.
Fadeyev VV, Morgunova TB, Melnichenko GA, Dedov II. Combined therapy with L-thyroxine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Hormones (Athens). 2010;9(3):245–52.
Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98(5):1982–90.
Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592–9.
Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G. REVIEW: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab. 2005;90(8):4946–54.
Joffe RT, Brimacombe M, Levitt AJ, Stagnaro-Green A. Treatment of clinical hypothyroidism with thyroxine and triiodothyronine: a literature review and metaanalysis. Psychosomatics. 2007;48(5):379–84.
Ma C, Xie J, Huang X, Wang G, Wang Y, Wang X, Zuo S. Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. Nucl Med Commun. 2009;30(8):586–93.
Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab. 2009;94(5):1623–9.
Appelhof BC, Peeters RP, Wiersinga WM, Visser TJ, Wekking EM, Huyser J, Schene AH, Tijssen JG, Hoogendijk WJ, Fliers E. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3′-triiodothyronine therapy. J Clin Endocrinol Metab. 2005;90(11):6296–9.
Carlé A, Faber J, Steffensen R, Laurberg P, Nygaard B. Hypothyroid patients encoding combined MCT10 and DIO2 gene polymorphisms may prefer L-T3 + L-T4 combination treatment - data using a blind, randomized, clinical study. Eur Thyroid J. 2017;6(3):143–51.
Wouters HJ, van Loon HC, van der Klauw MM, Elderson MF, Slagter SN, Kobold AM, Kema IP, Links TP, van Vliet-Ostaptchouk JV, Wolffenbuttel BH. No effect of the Thr92Ala polymorphism of Deiodinase-2 on thyroid hormone parameters, health-related quality of life, and cognitive functioning in a large population-based cohort study. Thyroid. 2017;27(2):147–55.
Burch HB, Burman KD, Cooper DS, Hennessey JV. A 2013 survey of clinical practice patterns in the management of primary hypothyroidism. J Clin Endocrinol Metab. 2014;99(6):2077–85.
de Jong NW, Baljet GM. Use of t4, t4 + t3, and t3 in the dutch population in the period 2005-2011. Eur Thyroid J. 2012;1(2):135–6.
Leese GP, Soto-Pedre E, Donnelly LA. Liothyronine use in a 17 year observational population-based study - the tears study. Clin Endocrinol. 2016;85(6):918–25.
Michaelsson LF, Medici BB, la Cour JL, Selmer C, Røder M, Perrild H, Knudsen N, Faber J, Nygaard B. Treating hypothyroidism with thyroxine/triiodothyronine combination therapy in Denmark: following guidelines or following trends? Eur Thyroid J. 2015;4(3):174–80.
Leese GP, Flynn RV, Jung RT, Macdonald TM, Murphy MJ, Morris AD. Increasing prevalence and incidence of thyroid disease in Tayside, Scotland: the Thyroid Epidemiology Audit and Research Study (TEARS). Clin Endocrinol. 2008;68(2):311–6.
Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med. 1993;119(6):492–502.
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. JAMA. 1995;273(10):808–12.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526–34.
Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract. 1993;43(368):107–9.
Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90(9):5483–8.
Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87(3):1068–72.
Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005;90(9):5489–96.
Walsh JP, Ward LC, Burke V, Bhagat CI, Shiels L, Henley D, Gillett MJ, Gilbert R, Tanner M, Stuckey BG. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab. 2006;91(7):2624–30.
Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol. 2009;169(6):749–55.
Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med. 2010;123(2):183.e181-189.
Weetman AP. Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol. 2011;74(4):411–8.
Engum A, Bjøro T, Mykletun A, Dahl AA. Thyroid autoimmunity, depression and anxiety; are there any connections? An epidemiological study of a large population. J Psychosom Res. 2005;59(5):263–8.
Pop VJ, Maartens LH, Leusink G, van Son MJ, Knottnerus AA, Ward AM, Metcalfe R, Weetman AP. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998;83(9):3194–7.
Ott J, Promberger R, Kober F, Neuhold N, Tea M, Huber JC, Hermann M. Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. 2011;21(2):161–7.
Lucke C, Hehrmann R, von Mayersbach K, von zur Mühlen A. Studies on circadian variations of plasma TSH, thyroxine and triiodothyronine in man. Acta Endocrinol. 1977;86(1):81–8.
Weeke J, Gundersen HJ. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol. 1978;89(4):659–72.
Balsam A, Dobbs CR, Leppo LE. Circadian variations in concentrations of plasma thyroxine and triiodothyronine in man. J Appl Physiol. 1975;39(2):297–9.
Russell W, Harrison RF, Smith N, Darzy K, Shalet S, Weetman AP, Ross RJ. Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels. J Clin Endocrinol Metab. 2008;93(6):2300–6.
Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM. Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Exp Clin Endocrinol Diabetes. 2007;115(4):261–7.
Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metab. 1974;39(5):923–7.
Jonklaas J, Burman KD. Daily administration of short-acting liothyronine is associated with significant triiodothyronine excursions and fails to alter thyroid-responsive parameters. Thyroid. 2016;26(6):770–8.
Leggio GM, Incognito T, Privitera G, Marano MR, Drago F. Comparative bioavailability of different formulations of levothyroxine and liothyronine in healthy volunteers. J Endocrinol Investig. 2006;29(11):RC35–8.
Fadeyev VV, Morgunova TB, Sytch JP, Melnichenko GA. TSH and thyroid hormones concentrations in patients with hypothyroidism receiving replacement therapy with L-thyroxine alone or in combination with L-triiodothyronine. Hormones (Athens). 2005;4(2):101–7.
Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS. The dynamic pituitary response to escalating-dose TRH stimulation test in hypothyroid patients treated with liothyronine or levothyroxine replacement therapy. J Clin Endocrinol Metab. 2013;98(5):E862–6.
Cheng S-Y, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31(2):139–70.
Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid. 2004;14(4):271–5.
Wartofsky L. Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: are we a step closer to the magic formula? Thyroid. 2004;14(4):247–8.
Boulton DW, Fawcett JP, Woods DJ. Stability of an extemporaneously compounded levothyroxine sodium oral liquid. Am J Health Syst Pharm. 1996;53(10):1157–61.
Jha S, Waghdhare S, Reddi R, Bhattacharya P. Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis. Thyroid. 2012;22(12):1283–6.
Bains A, Brosseau AJ, Harrison D. Iatrogenic thyrotoxicosis secondary to compounded liothyronine. Can J Hosp Pharm. 2015;68(1):57–9.
Pappy AL, Oyesiku N, Ioachimescu A. Severe TSH elevation and pituitary enlargement after changing thyroid replacement to compounded T4/T3 therapy. J Investig Med High Impact Case Rep. 2016;4(3):2324709616661834.
Escobar-Morreale HF, del Rey FE, Obregón MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996;137(6):2490–502.
Celi FS, Zemskova M, Linderman JD, Babar NI, Skarulis MC, Csako G, Wesley R, Costello R, Penzak SR, Pucino F. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. Clin Endocrinol. 2010;72(5):709–15.
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010;95(1):186–93.
Hennessey JV. Historical and current perspective in the use of thyroid extracts for the treatment of hypothyroidism. Endocr Pract. 2015;21(10):1161–70.
Penny R, Frasier SD. Elevated serum concentrations of triiodothyronine in hypothyroid patients. Values for patients receiving USP thyroid. Am J Dis Child. 1980;134(1):16–8.
LeBoff MS, Kaplan MM, Silva JE, Larsen PR. Bioavailability of thyroid hormones from oral replacement preparations. Metabolism. 1982;31(9):900–5.
Lev-Ran A. Part-of-the-day hypertriiodothyroninemia caused by desiccated thyroid. JAMA. 1983;250(20):2790–1.
Smith SR. Desiccated thyroid preparations. Obsolete therapy. Arch Intern Med. 1984;144(5):926–7.
Shrestha RT, Malabanan A, Haugen BR, Levy EG, Hennessey JV. Adverse event reporting in patients treated with thyroid hormone extract. Endocr Pract. 2017;23(5):566–75.
Jackson IM, Cobb WE. Why does anyone still use desiccated thyroid USP? Am J Med. 1978;64(2):284–8.
Surks MI, Schadlow AR, Oppenheimer JH. A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement. J Clin Invest. 1972;51(12):3104–13.