Effects of leuprorelin acetate microspheres on sex hormones, secondary sexual characteristics, and predicted adult height in early and fast puberty girls: a real-world, single-arm, retrospective cohort study

Introduction

Puberty marks a critical period in the lifecycle, which is characterized by gonadarche and adrenarche (1). During this period, children attain both somatic growth and reproductive maturity (1). Pubertal onset is controlled by the hypothalamic gonadotropin-releasing hormone pulse generator and other factors, such as changes in energy balance and exposure to endocrine-disrupting chemicals (2). Globally, the timing of pubertal development tends to decrease in girls, and the same trend is also found in Chinese girls (3,4). Sex hormone changes in early and fast puberty girls promote the development of secondary sexual characteristics, which may influence their mental health (5). On the other hand, growth and bone maturation are facilitated in early and fast puberty girls, which can impair their adult height (6).

Early and fast puberty is characterized by the onset of pubertal development after the diagnostic age cutoff for central precocious puberty (CPP) (7.5 years in girls and 9 years in boys), accompanied by rapid pubertal progression with advancement to the next pubertal stage <6 months and bone age (BA) progression exceeding chronological age (CA) progression (7). According to the Chinese expert consensus, gonadotropin-releasing hormone analog (GnRHa) is recommended for the treatment of both CPP and early and fast puberty (7). Consensus statements on GnRHa use indicate that treatment improves final adult height in girls with early-onset CPP (before 6 years of age), whereas its benefit in later-onset cases remains controversial (8). For instance, some previous studies found that GnRHa did not affect final adult height (9,10), but other studies reported the improvement in final adult height after GnRHa treatment in early and fast puberty children (11,12). Therefore, more evidence is required to further evaluate the efficacy of GnRHa in early and fast puberty, especially its effect on adult height.

Boennuokang^® leuprorelin acetate microspheres, as the first generic and domestic product, have been approved for the treatment of several diseases, such as prostate cancer, endometriosis, and CPP. Of note, a previous study has shown satisfactory efficacy of Boennuokang^® leuprorelin acetate microspheres in the treatment of prostate cancer (13). Considering the inhibitory effect of leuprorelin on the hypothalamic-pituitary-gonadal (HPG) axis and its approved pediatric indication for CPP, it was hypothesized that Boennuokang^® leuprorelin acetate microspheres might serve as a potential regimen for early and fast puberty girls. However, clinical evidence is needed to support the use of this specific formulation in early and fast puberty girls. Considering the complexity of clinical decision-making and the individualized treatment strategies in early and fast puberty girls, real-world studies may provide additional reference for the clinical application of Boennuokang^® leuprorelin acetate microspheres in this population.

Accordingly, the present real-world study aimed to explore the effect of Boennuokang^® leuprorelin acetate microspheres on sex hormones and predicted adult height (PAH) in early and fast puberty girls. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0218/rc).

Methods

Patients

This was a real-world, single-arm, retrospective cohort study. From January 2022 to November 2023, 198 early and fast puberty children who were treated with Boennuokang^® leuprorelin acetate microspheres for more than one year were retrospectively enrolled. All children were consecutively recruited from The First Bethune Hospital of Jilin University. The inclusion criteria were: (I) diagnosed with early and fast puberty, which was defined as the onset of pubertal development after the diagnostic age cutoff for CPP (7.5 years in girls and 9 years in boys), accompanied by rapid pubertal progression with advancement to the next pubertal stage <6 months and BA progression exceeding CA (14). This definition was uniformly applied across all enrolled children; (II) treated with Boennuokang^® leuprorelin acetate microspheres for at least 1 year; (III) with complete follow-up data. The exclusion criteria were: (I) with a history of malignant disease; (II) with prior treatment with GnRHa other than Boennuokang^® leuprorelin acetate microspheres. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Bethune Hospital of Jilin University (No. XXXX XXXX). The guardians of each patient signed the informed consent.

Treatment and definition

Boennuokang^® leuprorelin acetate microspheres (3.75 mg per dose) were administrated once every 28 days. According to the actual conditions, such as advanced BA and CA, as well as the patient’s own wishes, a booster dose (3.75 mg) was given on the 15^th day after the first administration in 45 early and fast puberty children. The time point before the first administration was defined as T0, and 3, 6, 12, and 18 months after the first administration were defined as T1, T2, T3, and T4, respectively.

Data collection and calculation

Characteristics of early and fast puberty children were collected from the electronic medical record, including age, sex, height, weight, BA, menarche, age of secondary sexual characteristics onset, Tanner stage (breast), length of uterus, PAH, genetic target height (GTH), height of father, height of mother, and age of mother’s menarche. Height and weight were measured by trained clinical staff. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol were measured in the hospital’s central biochemical laboratory using standardized assays with routine internal quality control. Uterine length was measured by pelvic ultrasonography in the radiology department. Tanner staging was assessed by a trained pediatric endocrinologist using a standardized clinical evaluation protocol. BA was assessed using the Greulich-Pyle atlas method (15), and PAH was calculated using the Bayley-Pinneau method (16), without blinded or duplicate evaluation. Additionally, LH, FSH, and estradiol levels were collected. Body mass index (BMI), BA/CA ratio, loss in growth potential (GTH minus PAH), and growth velocity [calculated using the formula: height at follow-up (cm) – height at diagnosis (cm) / time interval (year)] were calculated at each individual time point.

Evaluation

Longitudinal assessments were based on routinely collected clinical records and performed at T0 (before the first administration) and every 3 months (±2 days) in the first 6 months, and every 6 months (±2 days) thereafter. BA was assessed every 6 months (±2 days) after the first administration. Based on the collected data at T0, T1 (3 months after the first administration), T2 (6 months after the first administration), T3 (12 months after the first administration), and T4 (18 months after the first administration), the efficacy of Boennuokang^® leuprorelin acetate microspheres was evaluated. Missing follow-up assessments and attrition occurred during the study. LH, FSH, and estradiol were defined as the primary outcome to explore the effect of Boennuokang^® leuprorelin acetate microspheres on the HPG axis. The secondary outcomes included BA, BA/CA ratio, growth velocity, PAH, loss in growth potential (GTH minus PAH), Tanner stage, the length of uterus change, and BMI, which were used to evaluated the effect of Boennuokang^® leuprorelin acetate microspheres on height benefit, secondary sexual characteristics, and body weight.

Statistical analysis

SPSS ver.26.0 (IBM, USA) was used for data analysis. GraphPad Prism ver.9.0 (GraphPad, USA) was applied to plotting figures. No sample size calculation was performed. All eligible patients during the study period were consecutively included. Normality of continuous variables was assessed using the Shapiro-Wilk test. For T1, T2, T3, and T4 estradiol data that were below the lower limit of detection, the lower limit was used for the final analysis, consistent with commonly used substitution approaches in clinical research (17). The paired t-test and Wilcoxon signed-rank test were used to compare variables at individual time points with T0. The Freidman test and repeated-measure analysis of variance (ANOVA) were used as omnibus tests to compare variables over time. Sphericity was assessed using Mauchly’s test, and when violated, Greenhouse-Geisser correction was applied. The Kruskal-Wallis test and ANOVA test were used to compare variables among three subgroups at T0 to T4. Missing follow-up data were handled using an available-case analysis approach. Given the exploratory nature of this retrospective study, no formal adjustment for multiple comparisons was performed. A two-sided P value <0.05 indicated statistical significance.

Results

Flowchart

A total of 300 early and fast puberty girls receiving Boennuokang^® leuprorelin acetate microspheres between January 2022 and November 2023 were screened. Subsequently, 102 girls were excluded due to the treatment duration less than 1 year, and 198 girls were included in final analysis. No attrition occurred at T0, T1, T2, or T3, while 26 girls attrited at T4 (Figure S1). The median [95% confidence interval] follow-up duration was 18 [18–18] months.

Clinical features

The mean age of early and fast puberty girls was 9.73±0.99 years; a total of 10.10% of girls were aged ≥8–<9 years, 64.14% of girls were aged ≥9–<11 years, and 25.76% of girls were aged ≥11 years. Their BMI was 19.29±2.50 kg/m². The BA was 12.08±0.82 years, and the BA/CA ratio was 1.25±0.12. A total of 44 (22.22%) girls experienced menarche, and the other 154 (77.78%) girls did not experience that. The age of secondary sex characteristics onset was 9.69±0.99 years. There were 5 (2.53%), 43 (21.72%), 113 (57.07%), and 37 (18.69%) girls with a tanner stage B2, B3, B4, and B5, respectively. The PAH and GTH were 151.30±3.91 and 157.76±4.09 cm, respectively. Detailed information on subjects is shown in Table 1.

Number of girls with available data at each time point

At T0 and T1, all 198 girls had complete data. At T2, FSH were missing in 1 girl, PAH and GTH-PAH data were missing in 5 girls, and BA/CA ratio and uterus length change data were missing in 3 girls. At T3, uterus length change data were missing in 3 girls. At T4, LH, FSH, PAH, GTH minus PAH, BMI, BA/CA ratio, and growth velocity data were missing in 28 girls, estradiol data were missing in 26 girls, tanner stage data were missing in 30 girls, and uterus length change data were missing in 31 girls (Table S1).

LH, FSH, and estradiol at different time points

LH showed an overall decreasing trend after 18 months of treatment with Boennuokang^® leuprorelin acetate microspheres (P<0.001). After 3 months, median [quartile 1 (Q1)–quartile 3 (Q3)] basal LH levels were obviously decreased from 2.70 (2.23–3.51) to 0.84 (0.62–1.55) mIU/mL, and this reduction was maintained until month 18 (all P<0.001) (Figure 1A). In routine clinical practice, basal LH <0.3 IU/L was considered to indicate hormonal suppression, and 5.9% of girls had basal LH <0.3 IU/L at T4 in this study. Regarding FSH, it also exhibited a decreasing trend after 18-month treatment with Boennuokang^® leuprorelin acetate microspheres (P<0.001). Its median (Q1–Q3) basal levels profoundly reduced from 5.27 (4.82–6.10) to 2.81 (2.15–3.55) mIU/mL after 3 months of treatment, and the decrement was sustained until month 18 (all P<0.001) (Figure 1B).

Figure 1 LH and FSH in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. LH (A) and FSH (B) at T0, T1, T2, T3, and T4 in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. FSH, follicle-stimulating hormone; LH, luteinizing hormone; Q1, quartile 1; Q3, quartile 3; T0, before the first administration; T1, 3 months after the first administration; T2, 6 months after the first administration; T3, 12 months after the first administration; T4, 18 months after the first administration.

Estradiol was declined after treatment with Boennuokang^® leuprorelin acetate microspheres over time (P<0.001). Its median (Q1–Q3) levels were dramatically decreased from 163.50 (129.00–195.00) to 44.00 (36.70–71.00) pmol/L after 3 months of treatment; the reduction was maintained until month 18 (all P<0.001) (Figure 2).

Figure 2 Estradiol in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. Q1, quartile 1; Q3, quartile 3; T0, before the first administration; T1, 3 months after the first administration; T2, 6 months after the first administration; T3, 12 months after the first administration; T4, 18 months after the first administration.

Subgroup analyses of LH, FSH, and estradiol based on different age stratification

In three subgroups, LH, FSH, and estradiol showed a decreasing trend after 18-month treatment with Boennuokang^® leuprorelin acetate microspheres (all P<0.001). LH, FSH, and estradiol levels were dramatically decreased after 3 months of treatment compared to before treatment, and the reduction was sustained until month 18 in three subgroups (all P<0.001). After treatment, LH, FSH, and estradiol levels at any time point were not different among the three subgroups (all P>0.05) (Table S2).

Tanner stages and length of uterus at different time points

Among 113 early and fast puberty girls who were at the Tanner B4 stage before treatment, 2, 15, 14, and 14 girls transitioned to the B3 stage after 3, 6, 12, and 18 months of treatment. Among 37 early and fast puberty girls who were at the B5 stage before treatment, 16 girls transitioned to the B4 stage after 3 months of treatment; 17 girls transitioned to the B4 stage after 6 months of treatment; 1 girl transitioned to the B3 stage and 20 girls transitioned to B4 stage after 12 months of treatment; 4 girls transitioned to B3 stage and 10 girls transitioned to the B4 stage after 18 months of treatment. The proportions of early and fast puberty girls in the overall Tanner stage changed over time (P<0.001). The proportions of early and fast puberty girls in the Tanner stage B5 exhibited a decreasing trend over time. At any time point after treatment, the proportions of early and fast puberty girls in the overall Tanner stage were different compared to before treatment (all P<0.05) (Table 2).

The length of uterus exhibited a reducing trend over time after treatment with Boennuokang^® leuprorelin acetate microspheres (P<0.001). Moreover, the length of uterus was obviously decreased after 6 months of treatment compared to before treatment (21.47±4.26 vs. 31.97±6.55 mm), and the reduction was sustained until month 18 (all P<0.001) (Table 2).

Subgroup analyses of Tanner stage and length of uterus based on different age stratification

Only in girls aged ≥9–<11 years, the proportions of girls in the overall Tanner stage changed over time (P<0.001). However, in girls aged ≥8–<9 and ≥11 years, the proportions of girls in the overall Tanner stage remained unchanged over time (both P>0.05). The proportions of girls in the overall Tanner stage at some time points after treatment were different compared to before treatment in subgroups of girls aged ≥8–<9, ≥9–<11 , and ≥11 years (all P<0.05). The proportions of girls in the overall Tanner stage at any time point did not differ among the three subgroups (all P>0.05) (Table S3).

The length of uterus decreased over time in three subgroups (all P<0.001). The length of the uterus after treatment reduced compared to before treatment in all subgroups (all P<0.001). However, length of uterus at any time point did not differ among the three subgroups (all P>0.05) (Table S4).

BA, BA/CA ratio, and growth velocity at different time points

The BA/CA ratio showed an overall decreasing trend after treatment with Boennuokang^® leuprorelin acetate microspheres (P<0.001), and it decreased from 1.25±0.13 before treatment to 1.16±0.11 and 1.20±0.11 after 12 and 18 months of treatment (both P<0.001) (Figure 3). During treatment, BA showed an increasing trend (P<0.001). BA increased from 12.08±0.82 years before treatment to 12.40±0.76 and 12.76±0.68 years after 12 and 18 months of treatment (both P<0.001) (Table 3). Growth velocity exhibited a reducing trend over time (P=0.002). Its value reduced from 6.64±6.21 to 5.69±3.08 cm/year after 18 months of treatment (P=0.03) (Figure 4).

Figure 3 BA/CA ratio in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. BA, bone age; CA, chronological age; SD, standard deviation; T0, before the first administration; T1, 3 months after the first administration; T2, 6 months after the first administration; T3, 12 months after the first administration; T4, 18 months after the first administration.

Figure 4 Growth velocity in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. SD, standard deviation; T0, before the first administration; T1, 3 months after the first administration; T2, 6 months after the first administration; T3, 12 months after the first administration; T4, 18 months after the first administration.

PAH and loss in growth potential at different time points

PAH was improved after 18 months of treatment with Boennuokang^® leuprorelin acetate microspheres (P<0.001). After treatment, PAH at each time point (153.05±3.35, 154.12±3.33, 155.79±3.37, 157.37±3.33 cm) was improved compared to before treatment (151.30±3.92 cm) (all P<0.001) (Figure 5A). Loss in growth potential (GTH minus PAH) showed a decreasing trend over time (P<0.001); its value after 3 months of treatment was obviously decreased from 6.46±4.99 to 4.71±4.78 cm, and this reduction was maintained until month 18 (all P<0.001) (Figure 5B).

Figure 5 PAH and loss in growth potential (GTH minus PAH) in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. PAH (A) and loss in growth potential (GTH minus PAH) (B) at T0, T1, T2, T3, and T4 in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. GTH, genetic target height; PAH, predicted adult height; SD, standard deviation; T0, before the first administration; T1, 3 months after the first administration; T2, 6 months after the first administration; T3, 12 months after the first administration; T4, 18 months after the first administration.

Subgroup analyses of BA, BA/CA ratio, PAH, and loss in growth potential (GTH minus PAH) based on different age stratification

BA and PAH exhibited an elevating trend, while BA/CA ratio and loss in growth potential (GTH minus PAH) showed a decreasing trend after treatment in three subgroups (all P<0.05). Compared with before treatment, BA increased, BA/CA ratio decreased, PAH increased, and loss in growth potential (GTH minus PAH) decreased in all subgroups at some time points after treatment (all P<0.05). BA at any time point was the highest in girls aged ≥11 years, followed by girls aged ≥9–<11 years, and the lowest in girls aged ≥8–<9 years (all P<0.01), while the BA/CA ratio showed an inverse trend (all P<0.001). PAH after 18 months of treatment was the highest in girls aged ≥11 years, followed by girls aged ≥9–<11 years, and the lowest in girls aged ≥8–<9 years (P=0.008). Loss in growth potential (GTH minus PAH) after 18 months of treatment was the highest in girls aged ≥8–<9 years, followed by girls aged ≥11 years, and the lowest in girls aged ≥9–<11 years (P=0.02) (Table S5).

BMI at different time points

BMI increased after 3 months of treatment, then decreased until month 18 (P=0.005). BMI after 3 (P<0.001), 6 (P<0.001), and 12 (P=0.03) months of treatment were elevated compared to before treatment. However, BMI after 18 months of treatment was not different compared to before treatment (P=0.15) (Table 4).

Subgroup analyses of LH, FSH, and estradiol in children receiving a day-15 booster dose

A total of 45 early and fast puberty children received a day-15 booster dose, which might introduce treatment heterogeneity and potential confounding. Therefore, subgroup analyses of LH, FSH, and estradiol were conducted in these children to further evaluate the stability of the main findings. The changes in LH, FSH, and estradiol after treatment in children receiving a day-15 booster dose were consistent with those observed in the overall population (all P<0.001), suggesting that the main findings of hormonal suppression were relatively stable (Table S6).

Discussion

Suppressing gonadotropins and sex hormones are the main treatment goals of GnRHa (18,19). Mechanically, leuprorelin competitively binds with the GnRH receptor, leading to the inhibition of the HPG axis, ultimately contributing to the decrease in LH, FSH, and estradiol (20). According to previous studies, leuprorelin has exhibited satisfactory effects on inhibiting gonadotropins and sex hormones in CPP children (17,21-23). For example, FSH, LH, and estradiol reduced after the treatment of leuprorelin in CPP girls (22,23). In accordance with these previous studies, we also discovered that LH, FSH, and estradiol decreased over time in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. Moreover, we also conducted subgroup analyses based on age stratification (≥8–<9, ≥9–<11, and ≥11 years). It was found that the effect of Boennuokang^® leuprorelin acetate microspheres on suppressing LH, FSH, and estradiol was profound in three subgroups. This finding suggested that Boennuokang^® leuprorelin acetate microspheres were associated with the suppression of the HPG axis, regardless of the age stratification of early and fast puberty girls.

The development of breasts and changes in the uterus are crucial signs of early and fast puberty in girls (24). In this study, we found that after treatment with Boennuokang^® leuprorelin acetate microspheres, the proportions of early and fast puberty girls in the Tanner stage B5 and the length of uterus showed a decreasing trend over time. These findings indicated that Boennuokang^® leuprorelin acetate microspheres were related to pubertal development attenuation in early and fast puberty girls. Subgroup analyses indicated that changes in Tanner stage distribution were more evident in the 9-11-year group, whereas reductions in uterine length were observed across all age groups.

BA, a marker of bone maturation indicating the developmental stage of endochondral ossification, is associated with adult height (25,26). As reported by some previous studies, leuprorelin can reduce bone maturation and increase PAH in CPP children (22,27,28). For instance, the BA/CA ratio reduced after treatment with leuprorelin in CPP girls (23). Another previous study reported that the PAH at treatment initiation was 152.7±5.8 cm, which increased to 157.5±5.5 cm after treatment with leuprorelin in CPP girls (22). In this study, we found that the BA increased, but the BA/CA ratio and growth velocity reduced over time; additionally, PAH was improved, but the loss in growth potential (GTH minus PAH) decreased over time in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. A potential reason might be that Boennuokang^® leuprorelin acetate microspheres inhibited the growth plate fusion and closure, thereby delaying bone maturation and increasing potential adult height (26). However, it should be clarified that due to the retrospective design, the lack of an untreated control group, and the mixed dosing protocols, the effect of Boennuokang^® leuprorelin acetate microspheres on PAH cannot be separated from the natural slowing of late puberty. Therefore, further studies are required to validate this finding. In subgroup analyses, similar trends of BA, BA/CA ratio, PAH, and loss in growth potential (GTH minus PAH) over time were found in subgroups of early and fast puberty girls aged ≥8–<9, ≥9–<11, and ≥11 years.

Changes in BMI during GnRHa treatment are controversial in CPP children, according to previous studies (29-32). For instance, a previous study reported that BMI increased during GnRHa treatment in CPP children (33). However, a previous study discovered that BMI was not changed during GnRHa treatment in CPP children (34). In this study, we found that BMI was initially increased during the first 3 months, then gradually decreased in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. A previous study found that after 6- and 12-month treatment with GnRHa treatment, BMI was not different compared to its pretreatment level in CPP girls (35). In accordance with this previous study, we found that BMI after 18 months of treatment did not differ compared to before treatment in early and fast puberty girls who received Boennuokang^® leuprorelin acetate microspheres. This finding revealed that the long-term use of Boennuokang^® leuprorelin acetate microspheres was not related to changes in BMI.

In this study, 57.07% and 18.69% of girls were at Tanner stages B4 and B5, respectively, which raised concerns regarding the suitability of using Boennuokang^® leuprorelin acetate microspheres in these girls. However, it should be clarified that definite stopping criteria for GnRHa therapy in early and fast puberty girls have not been established according to the Expert Consensus on the Diagnosis and Treatment of Central Precocious Puberty [2022] (7). In clinical practice, decisions regarding continuation or discontinuation of GnRHa therapy are often individualized, taking into account growth potential, satisfaction with height, quality of life, and synchronization of pubertal development with peers. Therefore, girls with Tanner stages B4 and B5 were also included and received treatment.

Although several interesting findings were observed, limitations could not be omitted in this study. (I) This was a retrospective study. Thus, selection bias might exist in this study. (II) Our study did not follow up on the final adult height, preventing definitive conclusions regarding long-term height outcomes in early and fast puberty girls. (III) The GnRH stimulation test is a more robust method for confirming true HPG axis suppression during treatment. However, GnRH stimulation test data were not available because of the retrospective design. Further studies should incorporate GnRH stimulation testing during follow-up to provide a more comprehensive evaluation of central suppression after treatment with Boennuokang^® leuprorelin acetate microspheres. (IV) The lack of an untreated control group limited causal inference. Therefore, the observed improvements in pubertal and growth-related outcomes might partly reflect natural pubertal progression, which might have led to an overestimation of the treatment effect. (V) All children were from China, and only one formulation of leuprorelin was used. Therefore, the generalizability of our findings was limited. (VI) Because of the exploratory nature of this retrospective study, no formal adjustment for multiple comparisons was applied, which might lead to an increased risk of Type I error. (VI) The use of the lower limit to replace estradiol values below the limit of detection might introduce bias in both overall estimates and longitudinal comparisons. (VIII) The absence of an a priori sample size calculation might limit the robustness of the study, particularly in the context of subgroup analyses with relatively small sample sizes.

Conclusions

In conclusion, Boennuokang^® leuprorelin acetate microspheres are associated with the suppression of the HPG axis and increased PAH in early and fast puberty girls. However, given the retrospective design, the lack of a control group, and the absence of final adult height data, these findings require further validation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0218/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0218/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0218/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0218/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.The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Bethune Hospital of Jilin University (No. XXXX XXXX), informed consent was taken from the guardians of each patient.

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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