Effects of Long-term Combination LT4 and LT3 Therapy for Improving Hypothyroidism and Overall Quality of Life

Anam Tariq, DO; Yijin Wert, MS; Pramil Cheriyath, MD; Renu Joshi, MD


South Med J. 2018;111(6):363-369. 

In This Article

Abstract and Introduction


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: Compared with patients taking only LT4, 89.47% using synthetic therapy had therapeutic TSH (P < 0.05). Similarly, 96.49% using natural therapy had therapeutic TSH (P < 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.


According to the National Health and Nutrition Examination Survey, approximately 4.6% 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 some serum triiodothyronine (FT3). FT3 is the main active hormone at the cellular level, converted from FT4 by intracellular deiodinases. Synthetic liothyronine (LT3) is a synthetic drug that is identical to the hormone FT3. 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; however, approximately 5% to 10% of patients continue to have symptoms of hypothyroidism, despite normal TSH and FT4 levels.[4] This may occur because of dysfunctional deiodinase in a subset of hypothyroid patients, which is an important rationale for including active FT3 to improve symptoms in those patients. A subset of patients with hypothyroidism who continue to be symptomatic on LT4 therapy with normal TSH and FT4 or with normal or subnormal FT3; therefore, they will benefit from the addition of FT3 therapy (synthetic or natural).

In this retrospective study, we sought to measure the clinical and biochemical effects of the addition of LT3 therapy to the standard of care (LT4) in hypothyroid patients and to discover the differences between two different forms of FT3 combination therapies: desiccated thyroid extract (DTE), containing FT4, ("natural therapy") and LT4 with synthetic LT3 ("synthetic therapy"). A combination of LT4 and LT3 to improve the symptoms of hypothyroidism has been a topic of interest for several decades. Despite this interest, there remains a great deal of uncertainty regarding the best approach for the treatment of patients who do not respond to LT4 therapy alone, including the potential addition of FT3, whether synthetic or natural.

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.[6] Furthermore, in patients undergoing LT4 alone, the doses needed to normalize serum TSH were supraphysiological to compensate for the FT3 levels secreted from the thyroid gland.[7–10] Many patients reported feeling psychologically suboptimal on LT4.[11] They also concluded that variable levels of circulating FT4 and TSH, even within normal ranges of LT4, may affect psychological well-being, as measured by the General Health Questionnaire score.[12]

Bunevicius et al published a randomized controlled trial (RCT) in which combined LT4 and synthetic LT3 (12.5 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.[14] Similarly, a study of 697 patients found slight improvements in hypothyroid symptoms during 3 months of synthetic therapy, but these results were nonreplicable 1 year later.[15] Escobar-Morreale and colleagues reported that synthetic therapy appeared to have no beneficial effects on mood, quality of life, and psychometric performance of patients, as compared with LT4 alone.[16] A few subsequent studies showed hyperthyroidism with the use of combination therapy. The findings are controversial at best.[4,17–26]

In the last 5 years, there has been renewed interest in unraveling the uncertainty of combination therapies–synthetic and natural. In 2013, an RCT of 70 patients for 16 weeks showed no significant difference in symptoms and neurocognitive measures between LT4 monotherapy and DTE, although patients in the latter therapy group reported 4 pounds of weight loss on average, and subjectively, 48.6% reported preferring the period they were taking the DTE.[27] Despite the availability of natural therapy for >130 years, the Food and Drug Administration's lack of monitoring of FT4-FT3 dosage levels in these preparations has limited their use.[28] In 2014, the first observational study addressed the long-term (17 years) use of synthetic therapy in clinical practice.[29] Patients were predominantly younger with previous confounding hypothyroid-like symptoms of fatigue from mental disorders and depression, however.

The meta-analysis of combination therapy also has shown conflicting results. 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 meta-analysis in 2009 found some benefits in synthetic therapy for psychological and physical well-being and quality of life in 1243 patients; however, data were not statistically significant.[31] A third meta-analysis concluded that there was no significant difference in psychiatric symptoms among synthetic therapies.[32] A 2015 review summarized previous literature and data on LT4 and synthetic therapy, concluding use of LT4 monotherapy as the principal treatment of hypothyroidism and not combination therapy, unless future studies show clear benefits.[7]

The data on general well-being in hypothyroid patients on LT4 monotherapy are likewise inconclusive. Samuels et al demonstrated no clear association among TSH levels, cognition, and psychological performance while titrating on LT4 monotherapy.[33] For synthetic therapy, a randomized parallel design trial to evaluate FT3 substitution did not show any beneficial effects on psychometric performance, quality of life, and mood.[22] Nygaard and colleagues reported improvement in 7 of 11 scores pertaining to quality of life and depression with FT3 substitution compared with LT4 monotherapy.[26]

To summarize, there is no consensus, even among different international guidelines. In contrast to the American Association of Clinical Endocrinologists (AACE), the European consensus group suggests that LT4 monotherapy should serve as standard for hypothyroidism management, but they have suggested further researching LT4 and LT3 combinations in subsets of patients with symptoms.[34] The Italian Society of Endocrinology does not have evidence-based data, but recognizes that LT4 and LT3 therapy may be considered an experimental approach in overtly hypothyroid patients who have persistent symptoms despite adequate LT4 doses resulting in biochemical euthyroidism after exclusion of other specific causes for persistent symptoms.[35]