Use of the 36-Point Thyroid Symptom Questionnaire to Potentially Guide Optimal Thyroid Hormone Replacement Therapy.
Hoang T, Patel A, et al. • Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists • 2026
Patients on LT4 with moderate-to-severe symptoms despite normal TSH could consider a trial of combination therapy, while patients with low symptoms on LT4 should generally avoid combination therapy, as demonstrated by TSQ-36 scores across treatment groups.
Key Findings
Results
In cohort 1, patients with moderate-to-high symptoms on LT4 had significantly lower TSQ-36 scores on desiccated thyroid extract compared to levothyroxine.
Post hoc subgroup analysis of 2 previous randomized, double-blind, crossover studies with total n = 143
Patients were stratified into Low Symptoms (TSQ-36: 0-12), Moderate Symptoms (TSQ-36: 13-24), and High Symptoms (TSQ-36: 25-36) based on their score while on LT4
The Moderate-High Symptoms group in cohort 1 had significantly lower TSQ-36 scores on DTE vs LT4 (P = .01)
TSQ-36 was completed at the end of each treatment period in the context of normal thyroid stimulating hormone levels
Results
In cohort 2, the High Symptoms group had significantly lower TSQ-36 scores on both DTE and LT4+LT3 compared to LT4.
High Symptoms group had significantly lower TSQ-36 scores on DTE vs LT4 (P < .01)
High Symptoms group had significantly lower TSQ-36 scores on LT4+LT3 vs LT4 (P < .001)
Study design was a randomized, double-blind, crossover trial evaluating LT4, DTE, and LT4+LT3
Results
In cohort 2, the Moderate Symptoms group had significantly lower TSQ-36 scores on DTE compared to LT4.
The Moderate Symptoms group (TSQ-36: 13-24 on LT4) had significantly lower TSQ-36 scores on DTE vs LT4 (P = .02)
This finding was observed in cohort 2 of the post hoc subgroup analysis
Results
Patients with low symptoms on LT4 had significantly higher TSQ-36 scores (more symptoms) when switched to combination therapies.
The Low Symptoms group had significantly lower TSQ-36 scores on LT4 vs DTE (P = .03)
The Low Symptoms group had significantly lower TSQ-36 scores on LT4 vs LT4+LT3 (P = .02)
This indicates that patients with low baseline symptoms on LT4 fared worse on combination therapy
Results
Patients who preferred combination therapy had significantly higher TSQ-36 scores than patients who preferred LT4.
Treatment-blinded preference of therapy was stratified by TSQ-36 score on LT4
Patients preferring combination therapy had significantly higher TSQ-36 scores compared to those preferring LT4
This association suggests that symptom burden on LT4 may predict treatment preference
Discussion
The authors propose that persistent symptoms on LT4 may be due to a relative deficiency in triiodothyronine, which could be remedied by combination therapy.
Persistent symptoms despite TSH normalization are hypothesized to stem from relative T3 deficiency
Combination therapy options evaluated included DTE and LT4+LT3
The authors suggest the TSQ-36 can potentially be used to quantify patient symptoms and guide thyroid hormone therapy decisions
Methods
The study was a post hoc subgroup analysis of two previously conducted randomized, double-blind, crossover trials.
Total combined sample size was n = 143 across both cohorts
Treatments compared were LT4 monotherapy, DTE, and LT4+LT3 combination
The TSQ-36 is a 36-point questionnaire used to assess thyroid-related symptoms
All TSQ-36 assessments were completed at the end of each treatment period with normal TSH levels confirmed
Hoang T, Patel A, Spiro A, Watson N, Shakir M. (2026). Use of the 36-Point Thyroid Symptom Questionnaire to Potentially Guide Optimal Thyroid Hormone Replacement Therapy.. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. https://doi.org/10.1016/j.eprac.2025.09.007