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


Over the last 4 decades, treatment for hypothyroidism has evolved from the use of crude whole thyroid preparations (which provided both T4 and T3) to T4 monotherapy. This evolution is the result of technological advances, fear of iatrogenic hyperthyroidism due to excessive amounts of active T3, and pharmacological considerations (eg, half life), which enable convenient daily dosing for T4. During this evolution there remained evidence that patients treated adequately with T4 still experienced a number of symptoms, including deficits in cognition and mood, their ability to focus, and their general mental well-being.

An early landmark study by Bunevicius and colleagues demonstrated that T4/T3 combination therapy for hypothyroidism improved mood and cognition compared with T4 monotherapy in patients with chronic autoimmune thyroiditis and post-thyroid cancer total thyroidectomy.[19,44] However, the use of combination therapy remains controversial as several investigators were unable to reproduce these findings in 6 subsequent studies,[40–47] while 2 recent studies support a benefit for T4/T3 combination therapy in specific subsets of patients (Table 1).[46,47] In the recent large studies of thyroid function, investigators identified a substantial placebo effect,[47] which has made it difficult to delineate how combination therapy is associated with clinical benefits. It is also possible that combination therapy only works in a subset of patients because of yet unidentified mechanisms related to the complex and poorly understood T3 and T4 signaling in neurons. Such mechanisms may include differential signaling in response to T3 and T4 in neurons, including T4 signaling through αVβIII integrins induced by MAPK[70] and T3 signaling through PI3K.[68] Regardless of the mechanisms, T3 is increasingly being used as adjunct therapy in an increasing number of psychiatric diseases because of its positive effects on serotonin and the catecholamines.[78–84] Finally, it is possible that combination therapy has no benefits, as was suggested in recent meta-analyses.[86] However, because of our incomplete knowledge of thyroid signaling biology and the complexities of assessing the efficacy of thyroid hormone replacement (Figure 2), it remains to be definitively proven whether combination therapy should replace standard treatment for hypothyroidism.