Objective To explore the efficacy and safety of levothyroxine (L-T4) combined with desiccated thyroid extract (DTE) in patients with differentiated thyroid cancer (DTC) who had suboptimal response to long-term (≥6 months) thyroid-stimulating hormone (TSH) suppression therapy with L-T4 alone after surgery. MethodsA total of 123 eligible patients were prospectively enrolled and received TSH suppression therapy with DTE combined with L-T4. The Kaplan?Meier (KM) curve was used to analyze the TSH suppression rate and assess the efficacy of this combination therapy. The Thyroid-Related Patient-Reported Outcome-39 (THyPRO-39) questionnaire was used to assess the patient-reported symptoms before medication adjustment and at 1, 3, 6, 9, and 12 months after adjustment. ResultsAmong the 123 patients, 100 were ultimately included and completed follow-up, with a follow-up period of one year. After the first adjustment to L-T4+DTE combination therapy, the rate of TSH suppression was raised to 71.0% (71/100). The KM curve revealed that the TSH suppression rate gradually increased during the follow-up period, with a cumulative rate of 82.0%. The median TSH suppression time to reach the standard was 1.4 months. Eighteen patients (18.0%) still did not meet the target after multiple regimen adjustments. Univariate analysis indicated that sex and pre-treatment serum free triiodothyronine (FT3) levels were associated with the attainment rate of TSH suppression therapy (P<0.05). However, multivariate logistic regression analysis revealed that neither sex (OR=0.353, P=0.148) nor pre-treatment serum FT3 level (OR=2.596, P=0.101) was an independent influencing factor of TSH suppression attainment rate. Following L-T4+DTE combination therapy, the serum FT3 level significantly increased [(4.5±0.6) pmol/L vs. (5.5±1.1) pmol/L, P<0.001] but remained within the normal range, whereas the free thyroxine (FT4) level did not significantly change [(21.9±2.1) pmol/L vs. (21.5±3.0) pmol/L, P=0.075]. However, patients who did not achieve target levels exhibited a decrease in serum FT4 levels compared to baseline, and the magnitude of this decrease was significantly greater than that observed in the target-achieved group [–0.8 (–2.1, –0.9) pmol/L vs. –2.5 (–3.8, –0.8) pmol/L, P=0.022]. The questionnaire results indicated that the combined L-T4+DTE treatment regimen had no significant impact on overall quality of life scores during the follow-up period (χ2=4.006, P=0.548). Conversely, the hyperthyroidism symptom scores showed significant improvement over the treatment period (χ2=23.120, P<0.001), with the median scores demonstrating an overall downward trend. ConclusionFor postoperative DTC patients who fail to achieve TSH suppression with L-T4 monotherapy, L-T4+DTE combination therapy can significantly increase the TSH suppression attainment rate while alleviating thyrotoxicosis-related symptoms.