Combined T4 + T3 Therapy Versus T4 Monotherapy Effect on Psychological Health in Hypothyroidism

A Systematic Review and Meta-Analysis

Huiyu Lan; Junping Wen; Yaqian Mao; Huibin Huang; Gang Chen; Wei Lin


Clin Endocrinol. 2022;97(1):13-25. 

In This Article

Abstract and Introduction


Purpose: To evaluate whether T4 + T3 combination therapy had advantages in improving psychological health compared with T4 monotherapy.

Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science from January 2000 to March 2021, and updated in September 2021. The inclusion criteria (prospective study, published in English, had a T4 + T3 combination therapy test group and a T4 monotherapy control group, patients aged ≥18 years and with overt primary hypothyroidism, and published after January 2000) were applied by two reviewers; any disagreement was resolved by a third reviewer. The two reviewers independently extracted data using a standard data form and assessed the risk of bias using the Cochrane risk of bias tool. Coprimary outcomes included the psychological health measures of depression, fatigue, pain, anxiety and anger, measured using validated and reliable instruments.

Results: Eighteen of 2029 studies (883 patients) were included in the meta-analysis. No significant difference was found between T4 + T3 combination therapy and T4 monotherapy with regard to depression (standardized mean difference [SMD]: −0.06, 95% confidence interval [CI]: −0.18; 0.07), fatigue (SMD: 0.06, 95% CI: −0.13; 0.26), pain (SMD: −0.01, 95% CI: −0.24; 0.22), anxiety (SMD: 0.01, 95% CI: −0.15; 0.17) and anger (SMD: 0.05, 95% CI: −0.15; 0.24). Methodological heterogeneity had no influence on the results. The patients preferred combination therapy significantly.

Conclusions: Compared with T4 monotherapy, T4 + T3 combination therapy had no significant advantage in improving psychological health. For patients who are unsatisfied with LT4 monotherapy, the patient and the physician should make a joint decision concerning therapy.


Overt hypothyroidism, a common disease, is defined as thyroid stimulating hormone (TSH) concentration above the reference range and free thyroxin (FT4) level below the reference range.[1] The lifetime risk of developing hypothyroidism is about 5%, and the prevalence of hypothyroidism ranges from 1% to 2% in iodine-sufficient areas.[1,2] It is roughly 10 times more prevalent in women than in men.[1] Patients with hypothyroidism have an increased risk of suffering from psychological disorders, such as depression, anxiety and fatigue,[2,3] which are often overlooked by clinicians.

Since the 1970s, levothyroxine (LT4) has become the most commonly used drug for hypothyroidism due to its effectiveness, cheapness, long half-life and good compliance rate.[4] However, some patients experience hypothyroid symptoms despite having normal TSH levels, and adjusting the dose of LT4 slightly helped in improving psychological health.[4,5] Although most previous studies and meta-analysis[6–8] showed disappointing results of the combination therapy in improving psychological health, patients' preference for combination therapy is evident.[9] We speculate that the methodological heterogeneity of included clinical studies in previous meta-analysis may have obscured the subtle advantages of combination therapy. This meta-analysis focused on exploring whether the combination therapy, compared with monotherapy, has an advantage in improving psychological health. Furthermore, we performed subgroup analyses to explore whether methodological heterogeneity, including the scales used, gender, ratio of T3−T4 administration or timing of T3 administration, impacted the results.