Combined T4 + T3 therapy versus T4 monotherapy effect on psychological health in hypothyroidism: A systematic review and meta‐analysis
Open accessAbstract
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.
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Three previous meta-analyses evaluated patient preference with conflicting results.
“Three previous metanalyses evaluated patient preference as reported in those RCTs comparing L-T4 vs L-T4 + L-T3, with conflicting results.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The passage following Figure 4 says patients preferred T4 + T3 therapy and describes that finding as consistent with previous meta-analyses [6–8]. It therefore contradicts the claim that those meta-analyses had conflicting results on patient preference. No page number is available in our copy. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe incidence of adverse effects/reactions indicated that L-T4 and L-T4 + L-T3 treatments were equally safe for patients with hypothyroidism.
“Moreover, the incidence of adverse effects/reactions indicated that both treatments were equally safe for patients with hypothyroidism (7,8).”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The Results report no significant difference in cardiovascular health between T4 monotherapy and T4 + T3 therapy. The discussion cautions that most included studies had short follow-up and excluded people at high cardiovascular risk. The paper does not report an overall incidence of adverse effects or establish that the treatments are equally safe in general. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe RCTs consistently demonstrated that L-T4 and L-T4 + L-T3 treatments were both equally effective based on patient-reported outcomes (PROs), such as questionnaires evaluating quality of life, mood, and cognition.
“The RCTs, which spanned up to several months, consistently demonstrated that L-T4 and L-T4 + L-T3 treatments were both equally effective based on patient-reported outcomes (PROs), such as questionnaires evaluating quality of life (QoL), mood, and cognition.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The Results (page unavailable) report no significant difference between treatments on questionnaire-based measures of depression, fatigue, pain, anxiety, and anger. But the paper does not establish that the treatments were equally effective across every RCT, and its analyzed outcomes do not include cognition. The discussion (page unavailable) also cautions that its quality-of-life conclusion assumes the scales used measured quality of life adequately. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLan et al found a significantly greater preference for combination treatment, with an RR of 2.47 (95% CI, 1.31-4.67), I2 of 86%, and a P value of less than .05.
“Despite these limitations, Lan et al (7) found a significantly greater preference for combination treatment, with an RR of 2.47 (95% CI, 1.31-4.67),I² of 86%, and a P value of less than .05.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The Results section reports significantly greater preference for combination therapy, with RR 2.47 and 95% CI 1.31–4.67; this supports the stated significance and P < .05. Our copy does not give an I² value of 86% for that result, so that numerical detail is unverified. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPatients with hypothyroidism prefer LT4+LT3 therapy over LT4 alone.
“Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [15]
A second meta-analysis of 18 studies (883 patients) concluded that compared with LT4 monotherapy, LT4+LT3 combination therapy was equally effective in improving psychological health.
“A second meta-analysis of these 18 studies (883 patients) also concluded that compared with LT4 monotherapy, LT4+LT3 combination therapy was equally effective in improving psychological health (15).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [15]
The present analyses performed a sensitivity analysis with the funnel plot to identify and eliminate RCTs contributing to elevated heterogeneity, an approach not followed in previous meta-analyses.
“Throughout the present analyses, we performed a sensitivity analysis with the funnel plot to identify and eliminate RCTs that contributed to an elevated heterogeneity (without affecting the robust preference for L-T4 + L-T3 and DTE), an approach that was not followed in the previous meta-analyses (7,8,32).”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The other 2 meta-analyses by Millan-Alanis et al and Lan et al did not consider patient preference as a primary objective, and neither focused on randomized RCTs.
“The other 2 meta-analyses by Millan-Alanis et al (8) and Lan et al (7) did not consider patient preference as a primary objective, and neither focused on randomized RCTs.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The study considered 5 additional RCTs not considered by Akirov et al, 5 additional RCTs not considered by the Millan-Alanis meta-analysis, and 4 additional RCTs not considered by Lan.
“We considered 5 additional RCTs not considered by Akirov et al (32), 5 additional RCTs not considered by the Millan-Alanis meta-analysis (8), and 4 additional RCTs not considered by Lan (7).”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
Neither Millan-Alanis et al nor Lan et al used funnel plots to reduce heterogeneity when treatment preference was evaluated.
“Neither used funnel plots to reduce heterogeneity when treatment preference was evaluated.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
Two previous meta-analyses included nonrandomized trials (quasi-experimental), potentially compromising the quality of the assessment.
“Moreover, 2 previous meta-analyses (7, 8) included nonrandomized trials (quasi-experimental), potentially compromising the quality of the assessment.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
The References section identifies previous meta-analyses, and §2.2 describes risk-of-bias assessment in this review. Neither says that two earlier meta-analyses included nonrandomized or quasi-experimental trials. Searches for those terms and for limitations of previous meta-analyses found no passage addressing that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measuredMillan-Alanis et al and Lan et al included one quasi-randomized study, and Lan et al also included 3 nonrandomized studies.
“Millan-Alanis et al and Lan et al included one quasi-randomized study, and the latter also included 3 nonrandomized studies.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [7]
Section 2.1 describes eligibility for prospective studies, and Section 2.2 describes risk-of-bias assessment, but neither identifies the included studies by randomization status. Searches for quasi-randomized and nonrandomized studies found no passage establishing that Lan et al. included one of the former and three of the latter. The cited paper's copy also does not establish the count attributed to Millan-Alanis et al. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Cited by
Sorted by citations
Emerging Therapies in Hypothyroidism
Bianco, A. C. (2024) · Annual Review of Medicine · doi:10.1146/annurev-med-060622-101007 · Cited by 36 · see citing works
Treatment Preferences in Patients With Hypothyroidism
de Lima Beltrão, F. E., Carvalhal, G., de Almeida Beltrão, D. C., de Lima Beltrão, F. E., Ribeiro, M. O., Ettleson, M. D., Ramos, H. E., & Bianco, A. C. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae651 · Cited by 15 · see citing works
- Authors
- Lan, H., Wen, J., Mao, Y., Huang, H., Chen, G., & Lin, W.
- Affiliations
- Fujian Medical University (CN)
- Department of Endocrinology Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University Fuzhou Fujian China
- Corresponding author
- Chen, Gang
- Lin, Wei
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2022-04-27
- Volume
- 97
- Issue
- 1
- Pages
- 13-25
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W4224223721
- Cited by
- 26
- References
- 23
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 5 · 2023: 5 · 2022: 1
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2018YFC2001100‐5)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- hypothyroidism, levothyroxine, triiodothyronine, mental health, depression, fatigue, pain, anxiety, anger, patient preferences
- MeSH terms
- Adolescent, Adult, Depression, Fatigue, Humans, Hypothyroidism, Pain, Prospective Studies
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