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

Perceived Improvements in Combination Therapy?

In contrast to the investigations summarized above, there are 2 recent studies supporting T3/T4 combination therapy over T4 monotherapy for hypothyroidism. In a randomized, double-blind, crossover trial in 28 women with overt primary hypothyroidism, Escobar-Marraeale and colleagues[46] compared the standard 100 μg daily T4 treatment with the combination of 75 μg T4 plus 5 μg liothyronine (T3) daily for 8 weeks; after this period they administered 87.5 μg T4 plus 7.5 μg T3 (add-on combination therapy) to every patient over the subsequent 8 weeks (Table 1). No improvement in primary or secondary end points was seen after combination therapy. However, 12 patients preferred the combination therapy, 6 preferred the add-on combination treatment, and 2 preferred the standard treatment (6 had no preference).[46] Thus, despite the absence of any measurable physiologic advantages, there was a distinct preference for combination therapy.

Concerned that many of the previous studies were underpowered, Saravanan and colleagues performed the largest study to date comparing combination therapy with T4 monotherapy (Table 1). They conducted a double-blind, randomized, and controlled trial in 697 patients with hypothyroidism. Patients received T4 monotherapy or 50 μg less of the original T4 dose plus 10 μg of T3.[47] After 3 months, the control group demonstrated an improvement in psychiatric scores (based on a General Health Questionnaire [GHQ]) compared to baseline (ie, placebo effect), which was sustained for 1 year.[47] Changes that could be attributed to the T3 intervention were more modest; they included improvements in the GHQ score and the Hospital Anxiety and Depression Analog Scale scores for mood, but the initial improvements were lost at 12 months.[47] Although these findings may be consistent with improvement, they do not provide conclusive evidence that combination therapy is beneficial compared to T4 alone. They also demonstrate a large and sustained placebo effect that may make the findings of thyroid hormone administration studies difficult to evaluate.[47]

Overall the clinical studies comparing T4/T3 combination therapy to T4 monotherapy therapy reviewed here are conflicting and do not justify changing currently accepted treatment practices. While differences in study design are a common theme in the discussions of these papers, the conflicting data may reflect our limited understanding of the effects of thyroid activity on the brain and the complexity of systemic and cellular regulation of T3 and T4. There are in fact numerous additional considerations that may affect the overall efficacy of thyroid hormone replacement therapy, which are summarized in Figure 2. Exemplifying 1 of these many aspects are recent studies of thyroid signaling at the molecular level in neurons.[48] This particular aspect is important, because the benefits seen with T4/T3 combination therapy have been largely psychological in nature and, thus, related to neurocognitive brain function.

Figure 2.

Challenges in thyroid hormone replacement therapy.