Thyroid Signaling Biomarkers in Female Symptomatic Hypothyroid Patients on Liothyronine versus Levothyroxine Monotherapy: A Randomized Crossover Trial

Betty Ann Bjerkreim, Sara Salehi Hammerstad, Hanne Løvdal Gulseth, Tore Julsrud Berg, Sindre Lee-Ødegård, Erik Fink Eriksen, Betty Ann Bjerkreim, Sara Salehi Hammerstad, Hanne Løvdal Gulseth, Tore Julsrud Berg, Sindre Lee-Ødegård, Erik Fink Eriksen

Abstract

Background: Levels of thyroid-stimulating hormone (TSH) are believed to reflect degree of disease in patients with hypothyroidism, and normalization of levels is the treatment goal. However, despite adequate levels of TSH after starting levothyroxine (LT4) therapy, 5-10% of hypothyroid patients complain of persisting symptoms with a significant negative impact on quality of life. This indicates that TSH is not an optimal indicator of intracellular thyroid hormone effects in all patients. Our aim was to investigate different effects of LT3 and LT4 monotherapy on other biomarkers of the thyroid signaling pathway, in addition to adverse effects, in patients with residual hypothyroid symptoms.

Methods: Fifty-nine female hypothyroid patients, with residual symptoms on LT4 monotherapy or LT4/liothyronine (LT3) combination therapy, were randomly assigned in a non-blinded crossover study and received LT4 or LT3 monotherapy for 12 weeks each. Measurements, including serum analysis of a number of biochemical and hormonal parameters, were obtained at the baseline visit and after both treatment periods.

Results: Free thyroxine (FT4) was higher in the LT4 group, while free triiodothyronine (FT3) was higher in the LT3 group. The levels of reverse triiodothyronine (rT3) decreased after LT3 treatment compared with LT4 treatment. Both low-density lipoprotein (LDL) and total cholesterol levels were reduced, while sex hormone-binding globulin (SHBG) increased after LT3 treatment compared with LT4 treatment. The median TSH levels for both treatment groups were within the reference range, however, lower in the LT4 group than in the LT3 group. We did not find any differences in pro-B-type natriuretic peptide (NT pro-BNP), handgrip strength, bone turnover markers, or adverse events between the two treatment groups.

Conclusion: We have demonstrated that FT4, FT3, rT3, cholesterol, and SHBG show significantly different values on LT4 treatment compared with LT3 treatment in women with hypothyroidism and residual symptoms despite normal TSH levels. No differences in general or bone-specific adverse effects were demonstrated. This trial is registered with NCT03627611 in May 2018.

Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this study.

Copyright © 2022 Betty Ann Bjerkreim et al.

Figures

Figure 1
Figure 1
Flow chart showing all subjects approached for the study.
Figure 2
Figure 2
A multiple line graph showing mean (±95% confidence intervals) serum levels of total cholesterol (TC), HDL cholesterol, and LD cholesterol in mmol/L measured at the baseline visit and after both treatment periods with LT4 and LT3.
Figure 3
Figure 3
A scatter dot plot showing the association between serum levels of LDL cholesterol and levels of free T3 at baseline (grey line), after LT4 treatment (orange line), and after LT3 treatment (blue line).
Figure 4
Figure 4
A scatter dot plot showing the association between serum levels of LDL cholesterol and levels of reverse T3 at baseline (grey line), after LT4 treatment (orange line), and after LT3 treatment (blue line).

References

    1. Bianco A. C., Salvatore D., Gereben B., Berry M. J., Larsen P. R. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews . 2002;23(1):38–89. doi: 10.1210/edrv.23.1.0455.
    1. Wiersinga W. M., Duntas L., Fadeyev V., Nygaard B., Vanderpump M. P. J. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. European Thyroid Journal . 2012;1(2):55–71. doi: 10.1159/000339444.
    1. Escobar-Morreale H. F., Del Rey F. E., Obregón M. J., De Escobar G. M. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology . 1996;137(6):2490–2502. doi: 10.1210/endo.137.6.8641203.
    1. Zulewski H., Muller B., Exer P., Miserez A. R., Staub J.-J. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and Controls1. Journal of Clinical Endocrinology & Metabolism . 1997;82(3):771–776. doi: 10.1210/jcem.82.3.3810.
    1. Smith R. N., Taylor S. A., Massey J. C. Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. BMJ . 1970;4(5728):145–148. doi: 10.1136/bmj.4.5728.145.
    1. Escobar-Morreale H. F., Botella-Carretero J. I., Gómez-Bueno M., Galán J. M., 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 . 2005;142(6):412–424. doi: 10.7326/0003-4819-142-6-200503150-00007.
    1. Clyde P. W., Harari A. E., Getka E. J., Shakir K. M. M. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism. JAMA . 2003;290(22):2952–2958. doi: 10.1001/jama.290.22.2952.
    1. Sawka A. M., Gerstein H. C., Marriott M. J., MacQueen G. M., Joffe R. T. 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. Journal of Clinical Endocrinology & Metabolism . 2003;88(10):4551–4555. doi: 10.1210/jc.2003-030139.
    1. Walsh J. P., Shiels L., Lim E. M., 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. Journal of Clinical Endocrinology & Metabolism . 2003;88(10):4543–4550. doi: 10.1210/jc.2003-030249.
    1. Siegmund W., Spieker K., Weike A. I., 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. Clinical Endocrinology . 2004;60(6):750–757. doi: 10.1111/j.1365-2265.2004.02050.x.
    1. Rodriguez T., Lavis V. R., Meininger J. C., Kapadia A. S., Stafford L. F. 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. Endocrine Practice . 2005;11(4):223–233. doi: 10.4158/ep.11.4.223.
    1. Saravanan P., Simmons D. J., Greenwood R., Peters T. J., Dayan C. M. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. Journal of Clinical Endocrinology & Metabolism . 2005;90(2):805–812. doi: 10.1210/jc.2004-1672.
    1. Valizadeh M., Seyyed-Majidi M. R., Hajibeigloo H., Momtazi S., Musavinasab N., Hayatbakhsh M. R. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocrine Research . 2009;34(3):80–89. doi: 10.1080/07435800903156340.
    1. Fadeyev V., Morgunova T., Melnichenko G., Dedov I. Combined therapy with L-thyroxine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Hormones . 2010;9(3):245–252. doi: 10.14310/horm.2002.1274.
    1. Kaminski J., Miasaki F. Y., Paz-Filho G., Graf H., Carvalho G. A. D. Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. Archives of Endocrinology and Metabolism . 2016;60(6):562–572. doi: 10.1590/2359-3997000000192.
    1. Ianuzzo D., Patel P., Chen V., O’Brien P., Williams C. Thyroidal trophic influence on skeletal muscle myosin. Nature . 1977;270(5632):74–76. doi: 10.1038/270074a0.
    1. Sokolov E. I., Zaev A. P., Ol’kha R. P., Sofieva I. E., Zhizhina S. A. [Hemodynamic mechanisms of the decrease in physical work capacity in hypothyroidism and thyrotoxicosis] Kardiologiia . 1988;28(8):63–67.
    1. Brenta G., Mutti L. A., Schnitman M., Fretes O., Perrone A., Matute M. L. Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism, and its response to L-thyroxine therapy. The American Journal of Cardiology . 2003;91(11):1327–1330. doi: 10.1016/s0002-9149(03)00322-9.
    1. Baldwin K. M., Hooker A. M., Herrick R. E., Schrader L. F. Respiratory capacity and glycogen depletion in thyroid-deficient muscle. Journal of Applied Physiology . 1980;49(1):102–106. doi: 10.1152/jappl.1980.49.1.102.
    1. Duntas L. H., Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Medical Clinics of North America . 2012;96(2):269–281. doi: 10.1016/j.mcna.2012.01.012.
    1. Duntas L. H. Thyroid disease and lipids. Thyroid . 2002;12(4):287–293. doi: 10.1089/10507250252949405.
    1. Lithell H., Boberg J., Hellsing K., et al. Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein-lipase activity in overt and subclinical hypothyroidism: the effect of substitution therapy. European Journal of Clinical Investigation . 1981;11(1):3–10. doi: 10.1111/j.1365-2362.1981.tb01758.x.
    1. Celi F. S., Zemskova M., Linderman J. D., et al. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of LiothyronineVersusLevothyroxine. Journal of Clinical Endocrinology & Metabolism . 2011;96(11):3466–3474. doi: 10.1210/jc.2011-1329.
    1. Bjerkreim B. A., Hammerstad S. S., Gulseth H. L., et al. Effect of liothyronine treatment on dermal temperature and activation of Brown adipose tissue in female hypothyroid patients: a randomized crossover study. Frontiers in Endocrinology . 2021;12 doi: 10.3389/fendo.2021.785175.785175
    1. Bjerkreim B. A., Hammerstad S. S., Gulseth H. L., et al. Effect of liothyronine treatment on quality of life in female hypothyroid patients with residual symptoms on levothyroxine therapy: a randomised crossover study. Frontiers in Endocrinology . 2022;13
    1. Celi F. S., Zemskova M., Linderman J. D., et al. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. Clinical Endocrinology . 2010;72(5):709–715. doi: 10.1111/j.1365-2265.2009.03700.x.
    1. McAninch E. A., Rajan K. B., Miller C. H., Bianco A. C. Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis. Journal of Clinical Endocrinology & Metabolism . 2018;103(12):4533–4542. doi: 10.1210/jc.2018-01361.
    1. Mach F., Baigent C., Catapano A. L., et al. ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis . 2019;290:140–205.
    1. Sutton-Tyrrell K., Wildman R. P., Matthews K. A., et al. Sex hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the study of women across the nation (SWAN) Circulation . 2005;111(10):1242–1249. doi: 10.1161/01.cir.0000157697.54255.ce.
    1. Haffner S. M., Katz M. S., Stern M. P., Dunn J. F. Association of decreased sex hormone binding globulin and cardiovascular risk factors. Arteriosclerosis: An Official Journal of the American Heart Association, Inc. . 1989;9(1):136–143. doi: 10.1161/01.atv.9.1.136.
    1. Alevizaki M., Mantzou E., Cimponeriu A. T., Alevizaki C. C., Koutras D. A. TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wiener Klinische Wochenschrift . 2005;117(18):636–640. doi: 10.1007/s00508-005-0421-0.
    1. Sarne D. H., Refetoff S., Rosenfield R. L., Farriaux J. P. Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. Journal of Clinical Endocrinology & Metabolism . 1988;66(4):740–746. doi: 10.1210/jcem-66-4-740.
    1. Bachmann G., Oza D. Female androgen insufficiency. Obstetrics & Gynecology Clinics of North America . 2006;33(4):589–598. doi: 10.1016/j.ogc.2006.09.001.
    1. Amin A., Chitsazan M., Taghavi S., Ardeshiri M. Effects of triiodothyronine replacement therapy in patients with chronic stable heart failure and low‐triiodothyronine syndrome: a randomized, double‐blind, placebo‐controlled study. ESC Heart Failure . 2015;2(1):5–11. doi: 10.1002/ehf2.12025.
    1. Flamant F., Cheng S.-Y., Hollenberg A. N., et al. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology . 2017;158(7):2052–2057. doi: 10.1210/en.2017-00250.
    1. Cappola A. R., Desai A. S., Medici M., et al. Thyroid and cardiovascular disease research agenda for enhancing knowledge, prevention, and treatment. Circulation . 2019;29 doi: 10.1089/thy.2018.0416.
    1. Vasikaran S., Eastell R., Eastell R., et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporosis International . 2011;22(2):391–420. doi: 10.1007/s00198-010-1501-1.
    1. Garnero P., Sornay-Rendu E., Chapuy M. C., Delmas P. D. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal of Bone and Mineral Research . 1996;11(3):337–349. doi: 10.1002/jbmr.5650110307.
    1. Engler D., Burger A. G. The deiodination of the iodothyronines and of their derivatives in man. Endocrine Reviews . 1984;5(2):151–184. doi: 10.1210/edrv-5-2-151.
    1. Inada M., Nishikawa M., Naito K., et al. Effect of 3, 5, 3′L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine. Endocrinologia Japonica . 1980;27(3):291–295. doi: 10.1507/endocrj1954.27.291.
    1. Jonklaas J., Bianco A. C., Bauer A. J., et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid . 2014;24(12):1670–1751. doi: 10.1089/thy.2014.0028.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren