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Effects of Long-Term Combination LT4 and LT3 Therapy for Improving Hypothyroidism and Overall Quality of Life
Open accessAbstract
OBJECTIVES: Hypothyroidism results in decreased mood and neurocognition, weight gain, fatigue, and many other undesirable symptoms. The American Association of Clinical Endocrinologists, the American Thyroid Association (ATA), and The Endocrine Society recommend levothyroxine (LT4) monotherapy as the treatment for hypothyroidism; however, after years of monotherapy, some patients continue to experience impaired quality of life. Combination LT4 and synthetic liothyronine (LT3) therapy or the use of desiccated thyroid extract (DTE), has not been suggested for this indication based on short-duration studies with no significant benefits. Our first observational study examined the role of combination therapy for 6 years in improving quality of life in a subset of a hypothyroid population without adverse effects and cardiac mortality. METHODS: An observational retrospective study examining patients prescribed thyroid replacements with serum triiodothyronine (FT3), LT4 with LT3 (synthetic therapy) or DTE (natural therapy), compared with LT4 alone in the United States from 2010 to 2016. Thyroid-stimulating hormone (TSH), serum thyroxine (FT4), and FT3 levels were documented for each patient in addition to any admissions of myxedema coma, thyrotoxicosis, or cardiovascular complications, such as arrhythmias, atrial fibrillation, and mortality. At the conclusion of the study, a cross-sectional interview assessed quality of life for each combination therapy through the Medical Outcomes Study Short Form-20 questionnaire. RESULTS: < 0.05). Less than 5% of patients had supratherapeutic FT3. None of the patients who had abnormally low TSH or elevated FT3 or FT4 levels had hospitalizations for arrhythmias or thyrotoxicosis. On the Medical Outcomes Study Short Form-20 questionnaire, >92% answered feeling "excellent, very good, or good" when questioned about their health while undergoing thyroid replacement compared with levothyroxine alone. CONCLUSIONS: This is the only retrospective study reported to use long-term (mean 27 months) thyroid replacements with combination therapy and to compare between the two forms of therapy: synthetic and natural. For patients undergoing either therapy, we did not identify additional risks of atrial fibrillation, cardiovascular disease, or mortality in patients of all ages with hypothyroidism.
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“Fortunately, it is possible using T4+T3 combination therapy to keep serum TSH, FT4, and FT3 within their normal range in ≥90% of patients [86].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [86]
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“published data about preference or improvement of symptoms with such therapy is entirely from uncontrolled (23), sparsely documented (25) or small studies (24).”
From Short-Term Time Trends in Prescribing Therapy for Hypothyroidism: Results of a Survey of American Thyroid Association Members (2019) · cites this paper as [25]
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Hollowell, J. G., Staehling, N. W., Flanders, W. D., Hannon, W. H., Gunter, E. W., Spencer, C. A., & Braverman, L. E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.2.489 · Cited by 4,279 · cited 1×
“6% of the US population has hypothyroidism.(1) Physiologically, the hypothalamus releases thyroid-releasing hormone, which produces thyroid-stimulating hormone (TSH) that subsequently enhances the thyroid gland’s production of largely inactivated serum thyroxine (FT4) and”
BackgroundGarber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567 · cited 2×
“All of the patients were hypothyroid as defined by the ATA criteria, with elevated TSH and normal or subnormal FT4 at the beginning of LT4 therapy.(2)”
BackgroundSaravanan, P., Chau, W. ‐., Roberts, N., Vedhara, K., Greenwood, R., & Dayan, C. M. (2002) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2002.01654.x · Cited by 514
Bunevičius, R., Kažanavičius, G., Žalinkevičius, R., & Prange, A. J. (1999) · New England Journal of Medicine · doi:10.1056/nejm199902113400603 · Cited by 482 · cited 1×
“5 μg) were used in 33 patients, improving mood, well-being, and psychometric functionality.(13) Another study in 2002 with a sample size of 10 thyroidectomized patients for the treatment of Graves disease showed similar positive effects of the synthetic therapy.”
Method2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism
Wiersinga, W. M., Duntas, L., Fadeyev, V., Nygaard, B., & Vanderpump, M. P. J. (2012) · European Thyroid Journal · doi:10.1159/000339444 · Cited by 427 · cited 1×
“For years, the American Thyroid Association (ATA) and European guidelines suggested monitoring TSH and FT4 to make clinical decisions for starting and monitoring therapy of hypothyroidism.(2,3) This classic monotherapy of levothyroxine (LT4) provides adequate control of symptoms for a majority of the population; howev…”
BackgroundFish, L. H., Schwartz, H. L., Cavanaugh, J., Steffes, M. W., Bantle, J. P., & Oppenheimer, J. H. (1987) · New England Journal of Medicine · doi:10.1056/nejm198703263161302 · Cited by 353
Grozinsky-Glasberg, S., Fraser, A., Nahshoni, E., Weizman, A., & Leibovici, L. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0448 · Cited by 296 · cited 1×
“The first, a 2006 meta-analysis analyzed 1216 patients in 11 RCTs resulting in no advantage of synthetic therapy in bodily pain, depression, anxiety, fatigue, quality of life, body weight, and serum cholesterol.(30) A second metaanalysis in 2009 found some benefits in synthetic therapy for psychological and physical w…”
BackgroundEscobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118353 · Cited by 287 · cited 1×
“LT4 was initially found to be suboptimal in normalizing FT4 and FT3 in hypothyroid rats.(5) Subsequently, researchers were able to restore euthyroidism with a combination of LT4 and synthetic LT3, resulting in lower doses of LT4 and a normalization of FT3.”
BackgroundEscobar-Morreale, H. F., del Rey, F. E., Obregón, M. J., & de Escobar, G. M. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641203 · Cited by 261 · cited 5×
“The primary outcomes of the study were whether combination therapy was effective in improving clinical signs and symptoms of hypothyroidism as documented in the clinic note; improvement in hypothyroidism symptoms via the SF-20 questionnaire; and adverse effects of clinical or biochemical hyperthyroidism, as measured b…”
BackgroundInfluentialWalsh, J. P., Shiels, L., Lim, E. M., Bhagat, C. I., Ward, L. C., Stuckey, B. G. A., Dhaliwal, S. S., Chew, G. T., Bhagat, M. C., & Cussons, A. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030249 · Cited by 210
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Research works printed but not linked: 1
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Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism
Idrees, T., Palmer, S., Maciel, R. M. B., & Bianco, A. C. (2020) · Thyroid® · doi:10.1089/thy.2020.0153 · Cited by 58
“The mean follow-up duration was 27 months (median 22; range 1–111 months) (98).”
BackgroundResultInfluentialThe relevance of T3 in the management of hypothyroidism
Salvatore, D., Porcelli, T., Ettleson, M. D., & Bianco, A. C. (2022) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00004-3 · Cited by 44
Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019) · Drugs in Context · doi:10.7573/dic.212597 · Cited by 41
Gluvic, Z. M., Obradovic, M. M., Stewart, A. J., Essack, M., Pitt, S. J., Samardzic, V. S., Šoškić, S., Gojobori, T., & Isenović, E. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.758043 · Cited by 42
“did not find any additional risk for atrial fibrillation and cardiovascular disease in patients on combined LT3+LT4 therapy (133).”
BackgroundMariani, G., Tonacchera, M., Grosso, M., Fiore, E., Falcetta, P., Montanelli, L., Bagattini, B., Vitti, P., & Strausś, H. W. (2021) · Journal of Nuclear Medicine · doi:10.2967/jnumed.120.251504 · Cited by 35
“Nevertheless, a subgroup of hypothyroid patients does not achieve good results with L-thyroxine therapy alone (72); in these patients, combination therapy with L-thyroxine and liothyronine (L-T3) might be considered (73,74).”
Background
Metadata
- Authors
- Tariq, A., Wert, Y., Cheriyath, P., & Joshi, R.
- Affiliations
- Harrisburg Hospital (US)
- Venue
- Southern Medical Journal
- Publisher
- Southern Medical Association
- Published
- 2018-06
- Volume
- 111
- Issue
- 6
- Pages
- 363-369
- ISSN
- 0038-4348 (ISSN-L)
- 1541-8243
- PMC
- PMC5965938
- OpenAlex
- W2806754702
- Cited by
- 43
- References
- 42
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 4 · 2019: 3
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Southern Medical Journal (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- hypothyroidism, levothyroxine, liothyronine, combination thyroid hormone therapy, desiccated thyroid extract, quality of life, triiodothyronine, thyroid-stimulating hormone, atrial fibrillation, cardiovascular complications, myxedema coma, thyrotoxicosis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Drug Therapy, Combination, Female, Humans, Hypothyroidism, Male, Middle Aged, Quality of Life, Surveys and Questionnaires, Retrospective Studies, Thyrotropin, Thyroxine, Triiodothyronine
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