The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

T4/T3 Combination Compared with T4 Monotherapy

The recent resurgence into hypothyroidism treatment research derives from the experience of clinicians who found that some patients remain symptomatic while on prescribed T4 replacement therapy. For example, 1 survey conducted in the United Kingdom revealed that patients treated with T4 had significantly more psychological morbidity compared with euthyroid controls.[37] This was supported by findings in animal models, where hypothyroid rats realized normal thyroid hormone levels on a combination of T3 and T4 (in the ratio normally secreted by the rat thyroid gland) but not with T4 monotherapy.[38] This led to a landmark study by Bunevicius and colleagues who assessed whether T4/T3 combination therapy had any advantages over T4 monotherapy for hypothyroidism (Table 1).[19] To compare therapies, they used a crossover study design with 33 patients on different regimens of monotherapy and combination therapy over 2 different 5-week periods.[19] Combination therapy was achieved by replacing 50 μg of the patient's usual T4 dose (ranging from 100–300 μg/day) with 12.5 μg of T3.[19] Patients who received combination therapy had lower total and free T4 levels and higher T3 levels than patients who received T4 monotherapy. It was reported that cognitive performance and mood were significantly improved or normalized after treatment.[19] These findings prompted a series of papers aimed at assessing the potential advantages of combination therapy over monotherapy for hypothyroidism.[19,39–43]

Following the landmark paper, Bunevicius and colleagues performed a second crossover trial in women who had undergone a subtotal thyroidectomy as a treatment for Graves' disease (Table 1).[44] In this study, T4 therapy consisted of either the patient's regular dose of T4 or combination therapy, which was achieved by replacing 50 μg of the usual T4 dose with 10 μg of T3. After a period of 5 weeks, the patients were crossed over blindly to the opposite treatment. In patients who received combination therapy, the severity of symptoms of hypothyroidism and hyperthyroidism had a tendency to decrease, as indicated by patient scores on a standard symptom scale. Mental status also tended to improve with combination therapy compared with monotherapy, based on apparent improvement in mood (indicated by Visual Analogue Scale [VAS] scores). However, there was no difference in cognitive performance improvement (indicated by improved scores on the Digit Symbol and Digit Span tests of the Wechsler Adult Intelligence Scale). Although this study was small (n=13), the authors concluded its findings were consistent with those of their earlier study in terms of demonstrating a relationship between T4/T3 combination therapy and improved mental function.[44]