Efficacy and influencing factors of recombinant human growth hormone therapy in children with Turner syndrome: a single-center retrospective cohort study

Introduction

Turner syndrome (TS) is a clinical disorder caused by abnormalities of the sex chromosomes, predominantly affecting females. The prevalence is estimated at approximately 1 in 3,000 to 1 in 2,500 live female births (1-3). The clinical manifestations of TS are highly heterogeneous, among which short stature is one of the most common features, affecting over 95% of patients to varying degrees (4). Inhibited growth often becomes apparent in early childhood, and without timely intervention, adult height remains approximately 20 cm below the population average, significantly impairing quality of life and psychological well-being (5).

Recombinant human growth hormone (rhGH) therapy has been widely recommended by international guidelines and expert consensus as the standard treatment for improving height outcomes in children with TS. Numerous prospective and long-term follow-up studies have demonstrated that rhGH therapy effectively promotes linear growth and increases adult height, with earlier initiation yielding superior results (6,7). These benefits contribute not only to improved physical development but also to enhanced quality of life and social adaptation (8). However, substantial interindividual variability in therapeutic response remains a major clinical challenge. Some patients achieve significant catch-up growth, whereas others show suboptimal outcomes despite long-term therapy (9). This indicates that multiple factors may influence rhGH efficacy, such as age at treatment initiation, baseline height standard deviation score (HtSDS), insulin-like growth factor-1 (IGF-1) levels, rhGH dosage, treatment adherence, and karyotype differences (10-13). Furthermore, concerns persist regarding the long-term metabolic safety of rhGH in clinical practice, particularly its potential effects on insulin resistance [homeostatic model assessment for insulin resistance (HOMA-IR)], glucose tolerance, and excessive elevation of IGF-1 levels, underscoring the need for comprehensive real-world monitoring.

Age at treatment initiation plays a central role in the present study. Although international guidelines generally recommend early initiation of therapy, typically before 4–6 years of age, the precise relationship between age at initiation and treatment duration in real-world cohorts remains insufficiently studied (14,15). It is still unclear whether earlier initiation merely prolongs the treatment period or fundamentally alters growth trajectories by enhancing growth plate plasticity.

Most existing studies are based on rigorously controlled prospective trials (6,7), whereas single-center real-world data can provide unique insights into longitudinal patterns and clinical influencing factors in a population managed under stable and uniform protocols. In this study, a generalized estimating equation (GEE) model was employed to evaluate the efficacy and metabolic safety of rhGH over 36 months, addressing several key gaps in the literature. Specifically, the study aimed to: (I) analyze longitudinal changes in growth and safety parameters during treatment; (II) identify major baseline and time-related factors affecting therapeutic outcomes; and (III) investigate potential interactions between age at treatment initiation and follow-up duration and their influence on final treatment response. The findings of this study are expected to inform and optimize individualized therapeutic strategies for children with TS. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0422/rc).

Methods

Participants

This single-center retrospective cohort study was conducted at Hebei Children’s Hospital, a tertiary pediatric medical center. We reviewed the clinical records of all pediatric patients diagnosed with TS between February 2014 and July 2024.

A total of 50 patients were included based on a consecutive sampling method. The patients ranged in age from 3 to 14 years. No formal sample size or power calculation was performed prior to the study due to its retrospective real-world design and the relative rarity of the condition; however, all eligible patients within the 10-year study window who met the following criteria were included to maximize statistical power.

The inclusion criteria were as follows: (I) female phenotype; (II) chromosomal karyotype showing partial or complete loss of one X chromosome, or other structural abnormalities; (III) clinical features including growth delay [height <−2 standard deviations (SDs)] and/or gonadal dysgenesis, or characteristic physical manifestations such as facial nevi, webbed neck, low posterior hairline, or cubitus valgus; (IV) treatment with rhGH for ≥6 months with complete clinical data available; and (V) at least one documented follow-up visit.

The exclusion criteria were as follows: (I) concomitant endocrine or genetic disorders affecting growth; (II) previous treatments potentially influencing height (e.g., sex hormone replacement therapy); and (III) poor adherence or premature discontinuation of therapy.

To ensure data integrity and minimize chart extraction errors, two independent researchers extracted the data using a standardized electronic form, and a third senior physician verified any discrepancies. The screening process of eligible patients is illustrated in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of Hebei Children’s Hospital (No. 2025042) and informed consent was taken from all the legal guardians of children.

Figure 1 Flowchart of patient selection process and follow-up distribution. The study initially identified 104 children with Turner syndrome. After excluding untreated patients and those without follow-up records, 50 patients were included in the efficacy analysis. Metabolic safety assessment was specifically performed on the fixed cohort of 33 patients who completed the 12-month follow-up. rhGH, recombinant human growth hormone.

Treatment protocol

All enrolled patients received rhGH (Changchun GeneScience Pharmaceutical Co., Ltd., Changchun, China). rhGH was administered subcutaneously once daily at an initial dose of 0.045–0.050 mg/kg/d (equivalent to 0.135–0.150 IU/kg/d). Clinical follow-up occurred every 6 months, during which the dosage was titrated based on growth velocity (GV), serum IGF-1 levels, and bone age (BA) assessment results.

Measurement and laboratory standardization

Clinical and laboratory characteristics were extracted from medical records at the time of rhGH initiation, including birth weight, chronological age, BA, and anthropometric measures. Height was measured to the nearest 0.1 cm using a wall-mounted stadiometer by trained endocrine nurses, and weight was measured using a calibrated digital scale. To ensure consistency, all biochemical analyses were performed at the central laboratory of Hebei Children’s Hospital using standardized automated chemiluminescence immunoassays and enzymatic methods. Measured parameters included serum IGF-1, glycated hemoglobin (HbA1c), fasting glucose (GLU), fasting insulin, and thyroid function [thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4)]. BA was assessed by experienced radiologists according to the Greulich-Pyle method.

Efficacy and safety outcomes

The primary efficacy endpoints were the changes in HtSDS (ΔHtSDS) and GV at 6, 12, 18, 24, 30, and 36 months. HtSDSs were calculated based on Chinese reference data for children.

The calculation formulas were as follows:
HtSDS = (measured height – mean height of age- and sex-matched population)/SD of reference population height
GV (cm/year) = (height at current visit – height at previous visit)/months between visits × 12
ΔHtSDS = HtSDS_{time point} − HtSDS_baseline

Given the importance of safety monitoring during rhGH therapy, this study analyzed safety parameters, including GLU, HbA1c, insulin resistance index (HOMA-IR), and IGF-1 levels. A stable subset of 33 patients with complete metabolic data at 12 months of treatment was specifically selected for paired analysis to evaluate potential disturbances in glucose homeostasis. Additionally, patient medical records were reviewed to identify adverse events, including intracranial hypertension, slipped capital femoral epiphysis, and thyroid dysfunction.

Statistical analysis

Data analyses were performed using the software SPSS 26.0 (IBM Corp., Armonk, NY, USA). The Shapiro-Wilk test was applied to assess normality of continuous variables. Normally distributed data were expressed as mean ± SD, whereas non-normally distributed data were presented as median [interquartile range (IQR)]. Categorical variables were expressed as frequency and percentage. Considering the retrospective real-world design and the unequal number of observations across follow-up time points, GEEs were used to analyze longitudinal changes in treatment outcomes and to identify factors influencing rhGH efficacy. Candidate variables for the multivariable GEE models were selected based on clinical relevance and a significance threshold of P<0.10 in univariable analyses. Multicollinearity among predictors was assessed using variance inflation factors (VIF), with a VIF <5 indicating acceptable collinearity. An interaction term “follow-up duration × age at rhGH initiation” was included in the GEE model to examine the differential time-dependent effects of initiation age on treatment outcomes (HtSDS, ΔHtSDS, GV). A two-sided P value <0.05 was considered statistically significant.

Results

Clinical characteristics

A total of 50 patients were included in this study. The baseline clinical characteristics are summarized in Table 1. The mean age at rhGH initiation was 8.73±3.24 years. Among the participants, 12 patients (24%) started treatment before the age of 6 years, and 38 patients (76%) were ≥6 years at initiation.

Efficacy of rhGH therapy

Continuous improvement in height, HtSDS, and ΔHtSDS was observed throughout the rhGH treatment period. At baseline, the mean height was 114.50±14.90 cm, and the mean HtSDS was −3.18±0.93. After 6 months of treatment, HtSDS increased to −2.54±0.96, with a ΔHtSDS of 0.56±0.32. The greatest improvement was observed at 30 months, when HtSDS rose to −1.63±0.84 and ΔHtSDS to 1.25±0.66. GV was highest during the first 6 months (10.34±2.68 cm/year) and subsequently declined over time, reaching 5.25±2.44 cm/year at 36 months (Table 2).

Safety and metabolic parameters

Metabolic safety was assessed by comparing parameters at baseline and after 12 months of rhGH therapy in a stable cohort of 33 patients (Table 3). GLU (4.83±0.50 vs. 4.87±0.40 mmol/L, P=0.59) and HbA1c levels [5.20% (IQR, 5.00–5.30%) vs. 5.20% (IQR, 4.95–5.35%), P=0.87] showed no significant changes over the first year of treatment. As expected, median IGF-1 levels increased markedly from 114.50 to 299.00 ng/mL (P<0.001), reflecting the physiological response to rhGH. Although a slight increase in HOMA-IR was observed [1.44 (IQR, 1.07–2.22) at baseline vs. 1.97 (IQR, 1.10–2.73) at 12 months, P=0.049], the median value remained well within the normal clinical range for pediatric patients. No serious adverse events, including impaired glucose tolerance or overt diabetes, were reported during the follow-up period.

Factors influencing the efficacy of rhGH therapy

HtSDS as the dependent variable

The GEE analysis revealed that both follow-up duration and baseline HtSDS were significantly and positively associated with HtSDS (all P<0.05). Compared with 6 months, HtSDS increased by 0.391, 0.545, 0.666, 0.831, and 0.901 at 12, 18, 24, 30, and 36 months, respectively (P<0.001 for all). For each 1-unit increase in baseline HtSDS, the mean follow-up HtSDS increased by 0.797 (P<0.001, Table 4).

ΔHtSDS as the dependent variable

GEE analysis indicated that follow-up duration was significantly and positively correlated with ΔHtSDS (all P<0.05). Compared with 6 months, ΔHtSDS increased by 0.398, 0.401, 0.721, 0.878, and 0.951 at 12, 18, 24, 30, and 36 months, respectively (P<0.001 for all, Table 5).

GV as the dependent variable

Follow-up duration was significantly and negatively associated with GV (all P<0.05). Compared with 6 months, GV decreased by 3.998, 5.299, 3.986, and 5.181 cm/year at 18, 24, 30, and 36 months, respectively (P<0.001 for all, Table 6).

Interaction effect between rhGH initiation age and follow-up duration

HtSDS as the dependent variable

To further investigate whether the age at rhGH initiation affects the temporal change in HtSDS, a GEE model including the interaction term “follow-up duration × age at rhGH initiation” was established. The interaction effect was statistically significant [Wald χ²=155.271, degrees of freedom (df) =6, P<0.001]. Parameter estimates indicated that the interaction coefficients were negative and significant during the early follow-up period (6–18 months) (β=−0.148 to −0.087, P<0.05). Specifically, each additional year in initiation age was associated with a 0.087–0.148 lower HtSDS on average (Table 7).

ΔHtSDS as the dependent variable

To examine whether the trajectory of ΔHtSDS differs by rhGH initiation age, a significant interaction between follow-up duration and initiation age was also observed (Wald χ²=132.391, df=6, P<0.001). Parameter estimates showed that this interaction was negative and significant only during the early phase (6 months), where each 1-year delay in initiation age resulted in a 0.071 lower ΔHtSDS [β=−0.071, 95% confidence interval (CI): −0.134 to −0.009, P=0.02, Table 7].

GV as the dependent variable

The interaction effect between follow-up duration and initiation age on GV was also significant (Wald χ²=70.719, df=6, P<0.001). Although no significant interaction was detected in the early follow-up period (6–18 months, P>0.05), the coefficients gradually turned negative during the mid-to-late phase (24–36 months). At 36 months, the effect reached statistical significance (β=−0.520, 95% CI: −0.936 to −0.104, P=0.01), indicating that for each additional year of initiation age, GV decreased by 0.520 cm/year on average (Table 7).

Discussion

Significant efficacy and dynamic changes of rhGH therapy in children with TS

The present study demonstrated that treatment with rhGH significantly improved linear growth in children with TS. After 36 months of therapy, the mean height increased from 114.50±14.90 cm at baseline to 132.82±11.77 cm, whereas the HtSDS rose from −3.18±0.93 to −1.80±0.99, with a mean ΔHtSDS of 1.20±0.67. These findings indicate a marked improvement in growth status, consistent with previous reports (16-18), and further confirm the essential therapeutic value of rhGH as a standard treatment for TS. A dynamic growth pattern characterized by an initial rapid phase followed by a plateau was observed, in line with earlier findings (8,12). The GV was highest during the first 6 months of treatment (10.34±2.68 cm/year) and progressively declined to 5.25±2.44 cm/year at 36 months. Due to abnormalities in the sex chromosomes, patients with TS often exhibit dysfunction of the GH-IGF-1 axis. The early phase of rhGH therapy activates this axis and stimulates chondrocyte proliferation, leading to a “catch-up growth” effect (19). With prolonged treatment, BA advancement and epiphyseal closure reduce the proliferative potential of growth plate chondrocytes, eventually resulting in a stable GV level (20). These findings suggest that the early treatment period (6–12 months) serves as a critical window for efficacy evaluation and dose optimization. If suboptimal growth is observed during this phase, adherence, dosage, and other potential influencing factors, such as nutritional status, thyroid function, and karyotype variations, should be promptly assessed to avoid missing the optimal catch-up phase.

Relationship between treatment duration and therapeutic efficacy

The main-effect analysis revealed significant associations between treatment duration and the changes in HtSDS, ΔHtSDS, and GV. Compared with the 6-month follow-up, both HtSDS and ΔHtSDS increased progressively over 12–36 months, whereas GV showed a gradual decline. This indicates that height improvement during rhGH therapy is time-dependent, and long-term, standardized treatment is essential for achieving optimal adult height outcomes. Notably, although GV decreased over time, HtSDS continued to increase, suggesting a dynamic equilibrium characterized by a decreasing growth rate but cumulative height gains.

Relationship between baseline HtSDS and treatment response

A significant positive association was identified between baseline HtSDS and post-treatment improvement in HtSDS, indicating that children with higher baseline height (i.e., greater HtSDS) exhibited a more favorable response to rhGH therapy. This finding implies that pre-treatment growth status may partially determine sensitivity to exogenous GH. Physiologically, a higher baseline HtSDS is often associated with better nutritional status, a more intact GH-IGF-1 axis, and lower BA delay, all of which enhance responsiveness to rhGH. Conversely, a lower baseline HtSDS may reflect long-term growth restriction or concomitant factors such as thyroid dysfunction, poor nutrition, or diminished growth plate reactivity, leading to reduced GH sensitivity and slower standardized height improvement over the short term (21,22). Clinically, these results highlight the importance of considering baseline HtSDS, in addition to age at treatment initiation, as a predictive indicator of rhGH responsiveness in TS. For patients with lower baseline HtSDS, further assessment of nutritional, endocrine, and skeletal maturity factors is warranted. Individualized dose adjustment or combination therapy (e.g., low-dose estrogen initiation) may enhance GH responsiveness and ultimately improve overall treatment outcomes.

Interaction analysis of rhGH initiation age and follow-up duration

The interaction analysis in this study revealed a significant interaction between the age at rhGH initiation and follow-up duration, indicating that growth trajectories during treatment varied among children with different initiation ages. When HtSDS and ΔHtSDS were used as dependent variables, the interaction terms were significantly negative during the early treatment phase (6–12 months), suggesting that younger initiation age was associated with greater early improvement in standardized height (23). In contrast, in the GV model, a significant interaction was observed in the later treatment phase (36 months), indicating that older initiation age was associated with a more pronounced decline in GV. These findings suggest that the initiation age not only influences the overall efficacy of treatment but also shapes its temporal distribution pattern.

From a physiological perspective, early initiation of rhGH therapy allows treatment to begin at a stage when the epiphyseal plates remain open, GH receptor expression is abundant, and IGF-1 responsiveness is high, thereby facilitating rapid growth catch-up during the early treatment period (24,25). As BA advances and GH-IGF-1 axis feedback regulation strengthens, the rate of growth gradually slows. Conversely, late initiation is often associated with advanced BA and near-mature epiphyseal development, resulting in limited growth potential, weaker early response, and a more marked reduction in GV during the later stages of treatment. Therefore, the optimal timing for initiating rhGH therapy should be as early as possible (26). Early treatment maximizes growth plate plasticity and narrows the height gap with peers, contributing to improved self-esteem and treatment adherence from a psychosocial standpoint. However, late initiation does not preclude therapeutic benefit; patients can still achieve improvement through prolonged therapy, combination regimens (e.g., low-dose estrogen priming), or optimized dosing strategies. It is noteworthy that the observed decline in GV with extended treatment duration should not be interpreted as loss of efficacy but rather as a physiological stabilization process. Comprehensive assessment integrating IGF-1 levels and BA progression is recommended for accurate evaluation of therapeutic response (27,28).

Metabolic safety evaluation

Metabolic safety was assessed using the subset of 33 patients who had complete baseline and 12-month follow-up data for key metabolic parameters. These patients were selected to provide a stable cohort for evaluating safety while minimizing missing data.

The stability of GLU and HbA1c levels observed in this cohort suggests that rhGH, at the administered doses, does not acutely impair global glucose homeostasis. While we observed a statistically significant increase in the HOMA-IR index (P=0.049), this reflects the known physiological effect of growth hormone as an insulin antagonist. Importantly, the median HOMA-IR value remained well within the normal pediatric range, indicating that compensatory insulin secretion maintained normoglycemia. These results are consistent with previous large-scale observational studies (29,30), which indicate that although rhGH can modulate insulin sensitivity, the risk of developing overt diabetes remains very low in patients without pre-existing risk factors. Furthermore, no serious adverse events were recorded, confirming that the treatment was well tolerated in our real-world cohort.

Limitations

There are several limitations in this study. First, as a single-center retrospective study with a relatively small sample size (n=50), potential selection bias could not be completely excluded. In addition, the number of patients varied across follow-up time points, reflecting the real-world nature of retrospective clinical practice. Although GEEs were applied to account for repeated measurements with incomplete follow-up, the reduced sample size at later visits may have affected the precision of long-term efficacy estimates and introduced potential attrition bias. Second, the maximum follow-up duration was 36 months, and data on final adult height were unavailable. Third, the study did not include a control group, so it cannot be confirmed that the observed increases in height are entirely attributable to rhGH therapy. Caution should be exercised when interpreting the association between rhGH treatment and growth outcomes. Future research should involve larger sample sizes, multicenter and prospective study designs, and extended follow-up to adult height. Integration of genomic and pharmacogenomic analyses may help identify molecular biomarkers influencing rhGH responsiveness, thereby facilitating precision and individualized management for patients with TS.

Conclusions

In summary, this single-center retrospective study suggests that rhGH therapy is effective in improving linear growth in children with TS. The therapeutic response appears to be time-dependent, with earlier initiation and higher baseline height potentially leading to better outcomes. However, given the retrospective design and the absence of a control group, these findings should be interpreted cautiously and considered exploratory. Rather than providing firm clinical recommendations, our results provide preliminary evidence that individualized monitoring of growth patterns and metabolic safety may help inform clinical decision-making. Further prospective, multicenter studies are warranted to confirm these observations and to support the development of standardized management protocols.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0422/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0422/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0422/prf

Funding: This study was supported by the Special Research Project of National Health Commission Capacity Building and Continuing Education Center (No. GWJJZX20251001031).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0422/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. The study was approved by the Ethics Committee of Hebei Children’s Hospital (No. 2025042) and informed consent was taken from all the legal guardians of children.

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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(English Language Editor: J. Jones)