Factors influencing postoperative thyroid-stimulating hormone suppression therapy in low-risk papillary thyroid cancer after lobectomy

Introduction

Thyroid cancer represents the most prevalent malignancy of the endocrine system and has shown a significant rise in incidence worldwide in recent years (1,2). Papillary thyroid cancer (PTC) is the most common histological subtype of thyroid malignancy, accounting for 80–90% of all thyroid cancers, and generally has an excellent prognosis (3). The risk stratification system for differentiated thyroid cancer (DTC) established by the American Thyroid Association (ATA) guidelines has been widely adopted in clinical practice worldwide (4). According to the ATA guideline stratification system, DTC is categorized into three distinct risk groups: low, intermediate, and high risk. The ATA defines low-risk DTC as intrathyroidal papillary or follicular cancers without aggressive histology, evidence of local invasion, vascular invasion, distant metastases, and with fewer than five cervical nodal metastases (all <0.2 cm). With advances in imaging technology and the widespread adoption of proactive health screening, the vast majority of thyroid cancer cases are now diagnosed as low-risk thyroid cancer.

The recurrence rate in low-risk thyroid cancer varies from 1% to 10%, depending on clinicopathological variables (5,6). The latest research shows a trend toward more patients being treated with lobectomy alone and fewer receiving adjuvant radioactive iodine (RAI) (7-9). This trend will influence future recommendations for post-treatment management, including thyroid-stimulating hormone (TSH) suppression, utility of surveillance imaging, and role of thyroglobulin (Tg) measurement.

TSH suppression therapy is routinely implemented after surgical resection of DTC, because the proliferation of thyroid follicular cells is TSH-dependent. The majority of guidelines, including the ATA and European Society of Medical Oncology (ESMO) guidelines, recommends that low-risk patients should be maintained with a low-normal TSH level between 0.5 and 2.0 mU/L. Some studies have suggested that postoperative TSH levels are not associated with tumor recurrence in patients with low-risk PTC (10). The majority of cases are managed according to guideline recommendations. However, multiple factors influence postoperative TSH levels in patients with thyroid cancer, making the precise attainment of guideline-recommended TSH target levels a significant clinical challenge.

Accumulating evidence indicates that lifestyle factors, including diet, physical activity, and sleep, influence thyroid hormone levels in the general population (11-13). To date, few studies have systematically examined lifestyle factors impacting TSH levels following thyroid cancer surgery, and the available data show considerable variability.

This study was designed to analyze the potential influencing factors affecting TSH suppression outcomes in patients with postoperative low-risk PTC. The findings of this study may assist healthcare providers and patients in selecting optimal treatment strategies to improve clinical outcomes and enhance the quality of life. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0244/rc).

Methods

Study design and study subjects

Low-risk PTC patients who underwent lobectomy at The First Affiliated Hospital of Wannan Medical College between September 2024 and February 2025 were included in this cross-sectional study based on the inclusion and exclusion criteria. The data were sourced from inpatient electronic medical records at our hospital. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College {approval No. [2025]118}. Written informed consent was obtained from all participants or their legal guardians.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (I) patients who underwent lobectomy for the first time; (II) the postoperative pathological type of all patients was confirmed to have low-risk PTC; (III) after surgery, all patients were prescribed levothyroxine sodium tablets for TSH suppression therapy; and (IV) complete clinical data for all patients.

The exclusion criteria were as follows: (I) final thyroid pathology confirmed that the tumor was a non-papillary malignant thyroid carcinoma; (II) history of other malignant tumors; (III) history of preoperative use of drugs affecting thyroid function (amiodarone, lithium, estrogen, glucocorticoid, non-steroidal anti-inflammatory drugs, furosemide, and antineoplastic drugs); (IV) postoperative complications such as infection and chyle; (V) The patient undergone a second thyroid surgery due to disease recurrence and metastasis after the first thyroid surgery; and (VI) lack of complete clinical data.

Sample size determination

This was a cross-sectional study with a fixed enrollment period from September 2024 to February 2025. All consecutive low-risk PTC patients who met the eligibility criteria during this period were included. No a priori sample size calculation was performed; the final sample size (n=223) was determined by the number of eligible patients presenting within the study timeframe.

Research methods

According to the ATA recommendations based on initial risk stratification, for low-risk PTC patients undergoing thyroid lobectomy, the recommended target range for TSH suppression is 0.5–2.0 mU/L. Thus, this study compared various potential factors among three groups based on postoperative TSH levels: excessive TSH suppression group (TSH <0.5 mU/L), optimal TSH suppression group (TSH 0.5–2.0 mU/L), and insufficient TSH suppression group (TSH >2.0 mU/L). All the patients were initially admitted to the hospital for unilateral thyroid cancer. Preoperative evaluation should include contrast-enhanced computed tomography (CT) of the thyroid, thyroid and cervical lymph node ultrasonography, and thyroid function tests. The demographic characteristics included general characteristics (sex, age and comorbidities). Clinical laboratory characteristics included serum free triiodothyronine (FT3), free thyroxine (FT4), TSH, Tg and thyroid antibodies [thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb)]. Pathological characteristics included the longest tumor diameter, lesion site, multifocality, coexistence with Hashimoto’s thyroiditis, lymph node metastasis status, and BRAF V600E mutation status. Lifestyle characteristics included levothyroxine sodium dose, levothyroxine intake habits, dietary habits, sedentary time, physical activity levels, and sleep habits. We performed analyses to evaluate the association between these factors and postoperative TSH levels and to identify key factors. Comorbidities were defined as the presence of one or more of the following chronic conditions: hypertension, diabetes mellitus, coronary heart disease, or cerebral infarction. These conditions were documented based on patients’ medical histories and clinical records.

Diagnosis of Hashimoto’s thyroiditis

Hashimoto thyroiditis was defined as laboratory evidence of elevated TPOAb/TGAb levels along with either thyroid enlargement on imaging or histopathological features of lymphocytic infiltration and fibrotic transformation.

Measurement of postoperative serum TSH levels

Serum TSH and free thyroid hormone levels were measured 4–6 months after lobectomy. To ensure consistency, blood samples were drawn after patients received a morning dose of levothyroxine. Blood samples were collected intravenously between 8:00 AM and 4:30 PM for thyroid function testing after >6 hours of fasting and avoidance of moderate (24 hours prior) and vigorous (48 hours prior) physical activity. Blood samples were centrifuged and stored at 4 ℃ until further analysis. Circulating TSH, FT4, FT3, and Tg levels were determined using the Beckman Coulter DXI chemiluminescent immunoassay system.

Assessment of the diet

The dietary intake of each participant was assessed using 24-h recalls for three consecutive days (2 weekdays and 1 weekend day). The Mediterranean Diet Adherence (MDA) score was assessed using a validated scoring system developed by Trichopoulou et al. (14). This scale includes nine components: vegetables, legumes, fruits, nuts, cereals, fish, meat, dairy products, and alcohol. Values of 0 or 1 were assigned to each component using sex-specific median values as cutoffs (except for alcohol and dairy). For the six presumed beneficial components (vegetables, legumes, fruits, nuts, cereals, and fish), participants with intake at or above sex-specific medians received 1 point, whereas those with intake below sex-specific medians received 0. For meat intake, participants with an intake above the median were assigned a score of 0, whereas those with an intake below 1. Regarding alcohol consumption, men consuming 10–50 g/day and women consuming 5–25 g/day were given one point each. For dairy products, 1 point was assigned for daily intake between 5 and 25 g. The scores from all nine categories were summed to yield a total MDA score ranging from 0 to 9. The MDA score was calculated for all participants at recruitment and categorized into two levels: below the median + median (score 0–4) or above the median (score 5–9) (15).

Assessment of the physical activity levels, sedentary time and sleep habits

The levels of physical activity and sedentary time were evaluated according to World Health Organization (WHO) guidelines. Active level was defined as at least 150 min of moderate-intensity aerobic physical activity or at least 75 min of vigorous-intensity aerobic physical activity for 1 week. A low level was defined as physical activity with an intensity lower than the active level. Sedentary behavior is defined as any waking behavior characterized by an energy expenditure of ≤1.5 metabolic equivalents (METs) while in a sitting, reclining, or lying posture. The Pittsburgh Sleep Quality Index (PSQI), a validated self-report questionnaire, was used to assess the sleep quality. This scale consists of seven components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medication use, and daytime dysfunctions. The questionnaire comprises 19 items, with total scores ranging from 0 to 21. Higher scores indicate poorer sleep quality. Participants were instructed to recall their sleep status during the month prior to enrollment and complete a 19-item questionnaire. PSQI scores were calculated and recorded in detail. Based on the PSQI global scores, the patients were categorized into two groups: poor sleepers (score >5) and good sleepers (score ≤5) (16).

Statistical analyses

Data are presented as mean ± standard deviation (SD), median (interquartile range), or percentage, as appropriate. A comparative analysis was performed among the three groups. We conducted an analysis of variance (ANOVA) to compare the means of the variables across the three groups. The chi-squared test or Fisher’s exact test was used to test the statistical significance of the association among the three groups. All variables with P values less than 0.1 were then added to the multivariate logistic regression analysis. A multivariate logistic regression model was performed, and factors with a P value less than 0.05, were considered statistically significant. Additionally, 95% confidence intervals (CIs) were calculated. Statistical Package for Social Sciences (SPSS, version 24.0, IBM SPSS Statistics, IBM Corporation) was used to perform the analyses.

Efforts to address potential bias

To minimize selection bias, eligible patients were consecutively enrolled based on predefined inclusion and exclusion criteria. To reduce information bias, blood samples for thyroid function testing were collected under standardized conditions (fasting >6 hours, avoidance of physical activity, and consistent morning dosing of levothyroxine). All laboratory measurements were performed using the same Beckman Coulter DXI chemiluminescent immunoassay system. Dietary intake was assessed using 3-day 24-hour recalls to capture habitual intake, and validated instruments (MDA score, PSQI) were used for lifestyle evaluation. To control for confounding, multivariate logistic regression analyses included clinically relevant variables and those with P<0.1 in univariate analysis.

Results

Comparison of demographic characteristics among the three groups

A total of 223 patients who met the inclusion criteria were included in this study. According to the postoperative TSH suppression levels, the optimal TSH suppression group consisted of 63 patients, with 36 females (57.1%) and 27 males (42.9%). The average age of the optimal TSH suppression group was 43.84±10.36 years (27–66 years). The excessive TSH suppression group comprised 99 patients [89 females (89.9%) and 10 males (10.1%)]. The average age of excessive TSH suppression group was 45.38±9.95 years (25–71 years). The insufficient TSH suppression group comprised 61 patients [44 females (72.1%) and 17 males (27.9%)]. The average age of insufficient TSH suppression group was 44.67±12.72 years (19–71 years). As shown in Table 1, there were no statistically significant differences in age or marital status among the three groups (all P>0.05). The distribution of sex, body mass index (BMI) and comorbidities differed significantly among the groups (all P<0.05).

Comparison of preoperative clinical laboratory characteristics among the three groups

The average preoperative serum FT3 levels were 5.206±0.522 pg/mL (range: 3.630–6.470 pg/mL) in the excessive TSH suppression group, 5.367±0.529 pg/mL (4.110–6.420 pg/mL) in the optimal TSH suppression group, and 5.212±0.476 pg/mL (4.130–6.420 pg/mL) in the insufficient TSH suppression group. Preoperative serum FT4 levels showed no significant differences across TSH stratification groups, with mean ± SD (range) values of 16.507±2.051 pg/mL (12.540–22.420 pg/mL) in the excessive TSH suppression group, 16.989±2.098 pg/mL (13.360–22.690 pg/mL) in the optimal TSH suppression group, and 16.713±2.115 pg/mL (11.910–22.690 pg/mL) in the insufficient TSH suppression group. As shown in Table 2, there were no statistically significant differences in FT3, FT4, TG-Ab, TPO-Ab, or Tg levels among the three groups (all P>0.05). Preoperative TSH levels showed statistically significant differences among the three groups (P=0.01).

Comparison of pathological characteristics among the three groups

In Table 3, the pathological characteristics, including the longest tumor diameter, lesion site, central lymph node metastasis, Hashimoto’s thyroiditis, multifocality, and BRAF V600E mutations, are compared among the three groups. There were no statistically significant differences in the longest tumor diameter, lesion site, central lymph node metastasis, Hashimoto thyroiditis, or BRAF V600E mutation among the three groups (all P>0.05). The prevalence of multifocal lesions varied significantly among the three groups (P=0.02).

Comparison of lifestyle characteristics among the three groups

A comparison of lifestyle characteristics, including the dose of levothyroxine, levothyroxine intake habits, dietary habits, physical activity, sedentary time, and sleep habits, is presented in Table 4. There were no statistically significant differences in levothyroxine intake, dietary habits, and sleep habits among the three groups (all P>0.05). Levothyroxine dose, physical activity, and sedentary time showed statistically significant differences among the three groups (all P<0.05).

Multivariate logistic regression analysis of factors influencing TSH suppression therapy in low-risk PTC with lobectomy

Multivariate logistic regression analysis was performed using the optimal TSH suppression group as the reference group to analyze the factors associated with influencing TSH suppression therapy in low-risk PTC with lobectomy. Multivariate analysis revealed the significant predictors of postoperative TSH levels. Excessive postoperative TSH suppression in low-risk PTC is significantly associated with the female sex, higher levothyroxine dose (≥1.6 µg/kg/day), lower preoperative TSH levels, lower physical activity, and higher sedentary time. Conversely, insufficient TSH suppression was independently associated with higher BMI and lower levothyroxine dose (<1.6 µg/kg/day). Male patients had dramatically lower odds of achieving excessive suppression than did female [odds ratio (OR) =0.088, P<0.001]. A higher levothyroxine dose (≥1.6 µg/kg/day) significantly increased the likelihood of excessive suppression (OR =2.430, P=0.03) and reduced the risk of insufficient suppression (OR =0.414, P=0.048). Higher preoperative TSH levels were associated with decreased odds of excessive suppression (OR =0.577, P=0.004). Interestingly, both higher physical activity (OR =0.133, P<0.001) and lower sedentary time (OR =0.085, P<0.001) were strongly associated with a reduced likelihood of excessive suppression. Higher BMI predicted greater odds of insufficient suppression (OR =1.195, P=0.007). Comorbidities and tumor multifocality were not significantly associated with either outcome. The results are presented in Table 5.

Discussion

Treatment pathways for low-risk thyroid cancer have undergone significant de-escalation over the past two decades (17-19). Previously managed primarily with total thyroidectomy and selective adjuvant RAI therapy, this disease is now routinely treated with partial thyroidectomy alone, in carefully selected patients (20-22). This trend will undoubtedly shape future recommendations regarding TSH suppression (23). Nevertheless, TSH suppression therapy remains an important treatment option for low-risk DTC, according to guideline recommendations.

This study enrolled 223 low-risk patients with PTC who underwent lobectomy and TSH suppression therapy. Clinicopathological data of PTC patients, including demographic, preoperative clinical laboratory, pathological, and lifestyle characteristics, were analyzed to investigate the factors influencing TSH suppression therapy. These findings suggest that multiple factors were associated with postoperative TSH levels in this patient population.

Univariate analysis showed that sex and BMI were associated with postoperative TSH suppression in patients with thyroid cancer. Moreover, multivariate logistic regression analysis revealed that males had 91.2% lower odds of achieving TSH <0.5 mU/L vs. females (OR =0.088, 95% CI: 0.032–0.243; P<0.001), but comparable odds for TSH >2.0 mU/L (OR =0.571, 95% CI: 0.250–1.304; P=0.18). BMI was not associated with TSH <0.5 mU/L (OR =0.939 per 1-kg/m², 95% CI: 0.822–1.069; P=0.34), whereas each 1-kg/m² increase raised odds of TSH >2.0 mU/L by 19.5% (OR =1.195, 95% CI: 1.050–1.360; P=0.007). Several studies have shown that BMI and sex are predictors of TSH levels in thyroid cancer patients (24-26). Possible reasons may include estrogen levels influencing the body’s levothyroxine requirements and sex-based differences in physical activity (25). Body weight or BMI affects the oral clearance, apparent volume of distribution, and dose-normalized peak concentration of levothyroxine (27). For female patients, a higher body fat percentage and potential sex-based differences in drug distribution or clearance may contribute to lower levothyroxine requirements, thereby increasing the risk of oversuppression. Conversely, in patients with a higher BMI, a weight-based dose (µg/kg/day) may be inadequate, owing to an increased volume of distribution and possible alterations in drug absorption or metabolism. These findings highlight the limitations of a one-size-fits-all dosing approach and underscore the need for personalized strategies that account for body composition and potential pharmacokinetic variability.

A retrospective analysis of 168 patients undergoing lobectomy identified lower preoperative TSH levels as a significant predictor of postoperative TSH levels <2 mU/L (28). Similarly, a separate retrospective study of 268 patients with PTC revealed that elevated preoperative TSH levels necessitated higher postoperative TSH suppression doses (29). Our multivariate logistic regression analysis revealed that higher preoperative TSH levels independently predicted decreased probability of excessive TSH suppression (<0.5 mU/L), with an adjusted OR of 0.577 (P=0.004). Therefore, the required intensity of postoperative TSH-suppressive therapy exhibits an inverse relationship with preoperative TSH levels, wherein elevated baseline TSH necessitates higher levothyroxine doses, and lower preoperative levels permit dose reduction.

Levothyroxine sodium oral tablets serve as the first-line therapy for TSH-suppressive treatment following surgery for thyroid cancer. Zhang et al. demonstrated that levothyroxine sodium tablets doses below 1.4 µg/kg/day were significantly associated with an elevated risk of failure to achieve the target postoperative TSH level (P<0.05) (29). Our analysis demonstrated a significant dose-dependent therapeutic relationship between levothyroxine sodium dose and postoperative TSH control. Critically, doses ≥1.6 µg/kg/day significantly increased the likelihood of achieving excessive TSH suppression (TSH <0.5 mIU/L; OR =2.43, P=0.03) and reduced the risk of insufficient TSH elevation (TSH >2.0 mIU/L; OR =0.414, P=0.048) by 60%.

Previous studies demonstrated that lifestyle factors such as physical activity levels seem to be related to thyroid function particularly in young euthyroid adults (13,30). However, only a few studies have explored the correlation between physical activity and TSH suppression (31). Our study revealed that higher physical activity (OR =0.133, P<0.001) and shorter sedentary time (OR =0.085, P<0.001) were strongly associated with a reduced risk of failing to achieve a TSH level of <0.5. Physical activity, especially vigorous exercise, acts as a physiological stressor that disrupts the body’s homeostatic balance, ultimately prompting adaptive mechanisms to establish dynamic equilibrium (32).

We acknowledge that several of the principal findings, including the associations between levothyroxine dose, BMI, preoperative TSH levels and postoperative TSH suppression outcomes, are consistent with previously established relationships. The primary contribution of this study lies in the simultaneous evaluation of demographic, clinical, and lifestyle factors in the specific population of low-risk PTC patients undergoing lobectomy, particularly the inclusion of physical activity and sedentary behavior variables, which have been relatively understudied in the context of TSH suppression therapy. Nevertheless, the incremental novelty of these findings should be interpreted with appropriate caution.

The results of our study should be interpreted with caution owing to some limitations. First, the cross-sectional design precludes any causal inference from the observed associations. The relationship between physical activity and TSH suppression is particularly susceptible to reverse causality: it is equally plausible that patients with more profound TSH suppression (and consequently a subclinical hyperthyroid state) may have higher energy levels and engage in more physical activity, rather than physical activity itself driving lower TSH levels. Alternatively, both physical activity and TSH levels may be influenced by unmeasured confounders. Future prospective studies with repeated measurements are needed to establish the temporal sequence and directionality of these associations. Second, as our study enrolled predominantly Chinese participants from a single center, the findings may have limited generalizability. Third, lifestyle factors, including dietary habits, sedentary time, physical activity levels, and sleep habits were assessed via self-reported questionnaires (24-hour dietary recalls, MDA score, and PSQI). While we used validated instruments to minimize measurement error, self-reporting remains inherently susceptible to recall bias, social desirability bias, and misclassification. This is a particularly important limitation given that physical activity and sedentary time emerged as significant predictors in our analysis. The magnitude of these associations should therefore be interpreted with caution, and objective measures (e.g., accelerometry) would be valuable in future studies to corroborate these findings. Fourth, blood samples for TSH measurement were obtained after the morning levothyroxine dose, which may introduce variability in hormone measurements due to individual differences in drug absorption.

Conclusions

Using cross-sectional data from 223 patients, this study suggests that multiple factors may be associated with postoperative TSH management in low-risk PTC patients. Female sex, a higher levothyroxine dose, lower preoperative TSH levels, lower physical activity, and higher sedentary time were found to be associated with excessive postoperative TSH suppression. Higher BMI and lower levothyroxine dose were found to be associated with insufficient TSH suppression. These findings highlight the complex interplay between demographic, clinical, and lifestyle factors in postoperative TSH management. However, given the observational and self-reported nature of the data, these results should be considered hypothesis-generating rather than definitive. Prospective studies with objective lifestyle measurements are needed to confirm these associations before clinical implementation.

Acknowledgments

The authors thank all the patients included in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0244/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0244/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0244/prf

Funding: This study was supported by the Chronic Disease Management Research Project of the National Health Commission Capacity Building and Continuing Education Center Foundation (No. GWJJMB202510041125) and Integrated Development of Universities and Enterprises-QiLu Research Foundation (No. XQQL202415).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0244/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College {approval No. [2025]118}. Written informed consent was obtained from all participants or their legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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