Home Medicine Efficacy, adherence, and cost-efficiency of three growth hormone treatment strategies in children with idiopathic short stature: a retrospective cohort study
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Efficacy, adherence, and cost-efficiency of three growth hormone treatment strategies in children with idiopathic short stature: a retrospective cohort study

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Published/Copyright: January 28, 2026
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Journal of Pediatric Endocrinology and Metabolism
From the journal Journal of Pediatric Endocrinology and Metabolism Volume 39 Issue 3

Abstract

Objectives

The study compares the efficacy, adherence, and cost-effectiveness of three recombinant human growth hormone (rhGH) regimens in children with idiopathic short stature (ISS) to optimize treatments.

Methods

This retrospective cohort study involved 105 children with ISS who were divided into three groups: short-acting rhGH for 48 weeks (Group 1), PEG-rhGH for 48 weeks (Group 2), and sequential therapy (PEG-rhGH for 24 weeks + short-acting rhGH for 24 weeks) (Group 3). The primary endpoints were the annual changes in the height standard deviation score (ΔHtSDS) and height velocity (HV). Adherence was measured by the missed injection rate (%), and the cost-effectiveness analysis employed the cost-effectiveness ratio.

Results

After one year, all regimens improved HtSDS and HV (p<0.05), with Groups 2 and 3 showing better HV and ΔHtSDS than Group 1. Group 2 had the highest adherence (0 % missed rate), followed by Group 3 (0.14 %) and Group 1 (0.27 %). Missed injections were the only significant predictor of ΔHtSDS (β=−0.196, p=0.048). Financially, Group 3 had lower costs (¥64,730) and a better cost-effectiveness ratio than Group 2 (¥67,479). No serious adverse events occurred.

Conclusions

Sequential therapy offers efficacy and compliance benefits for long-acting rhGH while lowering costs, thus making it suitable for ISS treatment. Long-acting therapy is ideal for individuals with the financial means to support such treatment, whereas short-acting therapy is an option for individuals facing budgetary constraints. Future research should include longer follow-up and quality-of-life (QoL) assessments to improve the cost-benefit analysis.

Keywords: growth hormone; therapeutic efficacy; treatment adherence; cost-effectiveness

Introduction

Idiopathic short stature (ISS) is a childhood growth disorder of unknown cause. It is defined to refer to heights <−2 standard deviations (−2 SD) or <3rd percentile for age-, sex-, and ethnicity-matched peers, for which all known causes are excluded [1], 2]. ISS affects 1–3 % of children worldwide and accounts for 60–80 % of short stature cases [3]. Furthermore, it exposes children to psychological challenges such as teasing, social anxiety, and depression [4], 5]. Since recombinant human growth hormone (rhGH) was approved for ISS in 2003, this treatment has effectively increased adult height [6] and alleviated the associated psychological burdens in affected children [4]. However, traditional rhGH therapy requires daily injections because of its short half-life, thus leading to low adherence rates (36–49 %) resulting from discomfort and treatment burden [7], [8], [9], [10], which negatively impact growth velocity [11], [12], [13], [14]. Studies have reported that better adherence is correlated with higher height velocity and final adult height [15], 16]. To increase adherence to rhGH treatment, electronic autoinjection devices have been used; however, the degree of nonadherence remains high [12], thus leading relevant actors to focus on ways of reducing the injection frequency. The introduction of long-acting pegylated rhGH (PEG-rhGH) in 2014 improved adherence and growth but is costly [17], 18].

In clinical practice, some patients on long-acting rhGH switch to short-acting formulations because of financial constraints, thus leading to the emergence of a sequential long-to-short-acting rhGH treatment strategy. However, the efficacy, adherence, and cost-effectiveness of this sequential approach have not yet been evaluated systematically.

This study is the first to employ a retrospective cohort design and a pharmacoeconomic analysis to systematically compare the clinical value of three treatment strategies, i.e., daily short-acting therapy alone, weekly long-acting therapy alone, and long-acting-to-short-acting sequential therapy. By using evaluation metrics such as incremental cost-effectiveness analysis (ΔC/ΔE), this study aims to provide evidence-based support for clinical decision-making. These findings not only fill the highlighted gap in the evaluation of sequential combination therapy involving long-acting and short-acting rhGH but also serve as a crucial reference for efforts to optimize individualized treatment strategies for ISS.

Subjects and methods

Research design

This study involved a retrospective cohort of children with ISS who received treatment at Sichuan Provincial People’s Hospital from April 2022 to April 2024. The research was approved by the relevant Institutional Review Board (IRB) (No. 2022-Lun-Shen (Research)-64-1).

Sample size calculation

This cohort study compared one-year height increases among three treatments: daily rhGH, weekly PEG-rhGH, and sequential therapy. Sample size estimation was based on differences in the height standard deviation score (HtSDS), with expected changes of 0.55 SD for short-acting therapies and 0.98 SD for long-acting therapies [18], 19]. A minimal clinically important difference of 0.3 SD was established between the sequential and short-acting groups, in which context a mean change of 0.85 SD for sequential therapy was predicted. The within-group standard deviation (SD) was 0.5. Statistical power was calculated by conducting an analysis of variance (ANOVA) at α=0.05 and 80 % power, for which 24 subjects per group were required (total n=72). After a 10 % dropout adjustment, the final sample size was 27 participants per arm (total n=81).

Subject grouping

Patients were divided into three groups on the basis of their treatment regimen: (1) the long-acting rhGH therapy group (LAGH, which involved PEG-rhGH for 48 weeks), in which patients received PEG-rhGH at an initial dosage of 0.2 mg/kg/week by subcutaneous injection once per week for a total of 48 weeks; (2) the short-acting rhGH therapy group (SAGH, which involved rhGH for 48 weeks), in which patients received rhGH treatment at an initial dosage of 50 μg/kg/day by subcutaneous injection for 48 weeks; and (3) the sequential therapy group (PEG-rhGH for 24 weeks + rhGH for 24 weeks), in which patients received PEG-rhGH treatment at an initial dosage of 0.2 mg/kg/week by subcutaneous injection once per week for the first 24 weeks, followed by a switch to short-acting rhGH treatment at 50–70 μg/kg/day by subcutaneous injection for the subsequent 24 weeks.

Inclusion and exclusion criteria

Inclusion criteria:

  1. Satisfaction of the ISS diagnostic criteria, i.e., height <−2 SD or <3rd percentile (based on the 2005 Chinese Growth Charts for children from nine major cities);

  2. Annual growth rate ≤5.0 cm/year;

  3. Peak GH level ≥10.0 ng/mL in two different GH stimulation tests;

  4. Bone age: ≤9 years for girls and ≤10 years for boys; and

  5. Prepubertal status (Tanner stage I) and age ≥4 years.

Exclusion criteria:

  1. Abnormal liver/kidney function;

  2. Active hepatitis B infection;

  3. Severe diseases or disorders;

  4. Diabetes or other endocrine diseases;

  5. Short stature resulting from identifiable causes; and

  6. Treatment duration <1 year.

Outcome measures

The primary efficacy endpoints were height velocity (HV, cm/year) and annual change in height standard deviation score (ΔHtSDS), which were calculated at baseline and at 12 weeks by trained nurses. Secondary endpoints included changes in insulin-like growth factor-1 (IGF-1) levels, bone age (BA), and safety parameters. The missed injection rate (%) was calculated based on returned empty vials and prescription data, where one “injection” corresponds to one prescribed day. Regarding multidose vials, returned empty vials are converted into injection days based on the prescribed daily dose. For example, if a patient is prescribed 30 days of treatment and returns vials equivalent to 20 days, the missed injection rate is calculated as [(30−20)/30] × 100 %=33.3 %. Nevertheless, this method lacks objectivity because returned vials do not confirm actual medication use, which may lead to either overestimation or underestimation of true adherence depending on the circumstances.

Cost-effectiveness analysis

Annual treatment costs were based on medication usage, including drug and monitoring costs. Drug costs were calculated on the basis of the unit price, dosage, frequency, and duration, and the monitoring included quarterly checks of thyroid function, blood glucose, insulin, and IGF-1, alongside annual BA and pituitary MRI [20], 21]. All groups were monitored at the same hospital and faced similar costs. Effectiveness (E) was measured by reference to ΔHtSDS. The CEA used ΔHtSDS as the effectiveness measure, which was evaluated through the cost-effectiveness ratio (C/E=total cost/ΔHtSDS) and the incremental cost-effectiveness ratio (ICER=(C1 − C0)/(E1 − E0)), in which context lower ICER values indicate better resource efficiency with respect to additional gains in ΔHtSDS.

Statistical methods

Statistical analyses were performed using R software (R 4.3.3). Normality was assessed with the Shapiro–Wilk test. Normally distributed data are presented as means±SDs and were compared by ANOVA with Bonferroni correction. Missing data less than 5 % were imputed. Two-group comparisons were conducted using an unpaired t test. Non-normally distributed data are expressed as medians [M (P25–P75)] and were analyzed by Kruskal–Wallis or Mann–Whitney U tests. The Bonferroni method was used to correct p-values for Type I error inflation due to multiple comparisons, while effect sizes were measured using epsilon squared (ε2). Categorical data were analyzed using chi-square or Fisher’s exact tests. A multivariate linear regression model was created with ΔHtSDS as the dependent variable, adjusting for treatment regimens and baseline covariates such as missed injection rate, sex, age, bone age, IGF-1 level, and baseline HtSDS. A sensitivity analysis was conducted to address the limitations of the adherence measure, which is based on vial returns. We conservatively adjusted the missed injection rate in the LAGH group to 0.27 % (i.e., the upper quartile value of the sequential group) and reran the multiple linear regression model. Statistical significance was defined as p<0.05. We used a nonparametric bootstrap method with 1,000 iterations to assess the reliability of the primary outcome measure and calculate the 95 % bias-corrected and accelerated (BCa) confidence interval (CI). Additionally, G*Power 3.1 software was used for post hoc power analysis based on the observed effect size and sample size.

Results

Analysis of baseline characteristics

Of the 122 ISS children screened as part of this research, 105 satisfied the relevant criteria after others were excluded. The participants included those in the SAGH group (n=53), LAGH group (n=30), and sequential therapy group (n=22), all of whom completed follow-up.

The sequential group did not reach the planned sample size, whereas the other groups exceeded their targets.

A post hoc power analysis was conducted. On the basis of the observed effect size (ε2=0.096) and its conversion to Cohen’s f (0.33), alongside the total sample size (n=105), the post hoc power for the three-group comparison was 86.6 %, which exceeded the conventional threshold of 80 %. These results indicate that the total sample size considered in this study was adequate to detect the observed effect. Among the children who participated in this research, 60 were male and 45 were female; their median ages ranged from 5.13 to 6.1 years. BA was higher in the SAGH group, but the difference was not significant. HtSDS and IGF-1 levels were similar at baseline. Growth hormone dosages were consistent across the groups (Table 1).

Table 1:

Comparisons of related parameters before and after treatment across groups.

Parameter Short-acting group (rhGH for 48 weeks) (n=53) Long-acting group (PEG-rhGH for 48 weeks) (n=30) Sequential group (PEG-rhGH for 24 weeks + rhGH for 24 weeks) (n=22)
Pretreatment Posttreatment Pretreatment Posttreatment Pretreatment Posttreatment
Age, years 6.1 (5.1–7.2) 7.1 (6.1–8.2) 5.1 (4.4–6.7) 6.1 (5.4–7.7) 5.6 (4.5–6.5) 6.1 (5.4–7.7)
Height, cm 106.64 ± 9.01 116.42 ± 8.65a 102.57 ± 10.90 113.52 ± 10.19a 102.95 ± 7.50 114.05 ± 7.63a
BMI, kg/m2 12.32 (11.90–13.18) 14.88 (14.22–15.45)a 12.65 (11.67–13.79) 16.35 (14.96–18.38)a 11.74 (11.32–13.25) 17.10 (16.01–18.30)a
HtSDS −2.17 (−2.43 to −2.06) −1.34 (−1.78 to −1.06)a −2.30 (−2.66 to −2.04) −1.22 (−1.66 to −1.00)a −2.36 (−2.77 to −2.14) −1.24 (−1.56 to −1.06)a
Bone age, years 5.16 ± 1.40 5.94 ± 1.53a 4.54 ± 1.78 5.11 ± 2.17a 4.45 ± 1.51 4.97 ± 1.46a
IGF-1, ng/mL 98.6 (77.4–115) 226 (192–287)a 91.05 (61.8–124) 233 (162–361)a 81.2 (65.3–92.8) 194.5 (158–277.0)a
HV, cm/year 9.40 (8.50–10.60)b 10.25 (9.60–12.00) 11.20 (9.60–12.20)
ΔHtSDS 0.85 (0.65–1.04)b 1.02 (0.78–1.35) 1.20 (0.93–1.35)
Males 33 14 13
Females 20 16 9
Missed injection rate, % 0.27 (0–2.19)b 0.00 (0–0.27) 0.14 (0–0.27)
SAGH dose, μg/kg/d 50 (50–50) – 50 (50–54)
LAGH dose, mg/kg/week – 0.2 0.2

  1. rhGH, recombinant human growth hormone; HtSDS, height standard deviation score; IGF-1, insulin-like growth factor 1; HV, height velocity; BMI, body mass index; SAGH, short-acting rhGH; LAGH, long-acting rhGH. Data are presented as medians (interquartile ranges) or as means ± standard deviations. aSignificant difference (p<0.05) within the group compared to pretreatment. bSignificant difference (p<0.05) compared with the long-acting (PEG-rhGH for 48 weeks) and sequential (PEG-rhGH for 24 weeks + rhGH for 24 weeks) groups.

Evaluation of treatment efficacy

Improvement in growth parameters

Missing IGF-1 values (4.7 %) were replaced with the cohort median (221.2 ng/mL), maintaining distribution properties (Kolmogorov–Smirnov, p=1.0). After one year, HtSDS and IGF-1 levels significantly increased in all treatment groups (within-group p<0.05), but no significant differences in BA progression were found. HV varied. The LAGH group had 10.25 cm/year, and the sequential group had 11.20 cm/year, both were significantly greater (p<0.01) than the SAGH group at 9.40 cm/year. ΔHtSDS also showed significant differences. The LAGH group had 1.02, the sequential group had 1.20, both greater (p<0.05) than the SAGH group at 0.85. Differences in ΔHtSDS among groups had a medium effect size (ε2=0.096). No significant differences in ΔIGF-1 levels were noted (p>0.05), as shown in Table 1. In summary, long-acting rhGH therapy showed greater improvements in HV and HtSDS compared to short-acting rhGH. Bootstrap analysis indicated a robust primary effect estimate (95 % [BCa CI]: 0.1245, 0.5000), specifically reflecting the treatment regimen’s effect on ΔHtSDS; however, the question of whether the treatment regimen is a significant independent predictor of ΔHtSDS remains unanswered, and further adjustment for confounding factors is necessary.

Comparison of treatment adherence

We analysed missed injection rates to evaluate treatment adherence among the three therapeutic approaches over one year. The LAGH group exhibited nearly perfect adherence (median missed rate 0 %), whereas the SAGH group exhibited significantly worse adherence (median 0.27 %). The sequential regimen exhibited intermediate adherence (median 0.14 %), which was 48 % better than that the corresponding figure for the SAGH group. Statistical comparisons confirmed that the nonadherence exhibited by the SAGH group was greater than that exhibited by both the LAGH group and the sequential therapy group, although the latter two exhibited comparable levels of adherence. These findings indicate that long-acting PEG-rhGH formulations lead to better adherence than daily rhGH injections do (Table 1).

Multivariate linear regression analysis of the factors influencing growth hormone efficacy

A multivariate linear regression was conducted to identify predictors of treatment efficacy, with △HtSDS as the dependent variable. Baseline characteristics and treatment factors were used as independent variables. The model was valid, showing no multicollinearity or autocorrelation, and was statistically significant (R=0.52, adjusted R2=0.197, p<0.05), indicating that approximately 19.7 % of the variance in △HtSDS was explained by the model. Among the predictors, only the missed injection rate was significant (p<0.01) and negatively impacted △HtSDS. Differences among treatment regimens were not significant after statistical adjustments for baseline characteristics (p>0.05, Table 2). A sensitivity analysis conservatively set the LAGH group’s missed injection rate to the sequential group’s upper quartile (0.27 %) to address adherence measure limitations. After rerunning multivariate regression, neither LAGH (β=0.159, p=0.122) nor sequential groups showed significant differences from SAGH. The missed injection rate remained a significant independent predictor of ΔHtSDS (β=−0.205, p=0.036), with effect size and significance consistent with the original model (Supplementary Table 1).

Table 2:

Multivariate linear regression analysis of the factors influencing ΔHtSDS.

ΔHtSDS B β t-Value p-Value Tolerance VIF
Constant 1.315 3.201 0.002a
Sex 0.155 0.18 1.964 0.052 0.92 1.087
Age −0.003 −0.012 −0.067 0.947 0.239 4.178
Baseline HtSDS −0.12 −0.12 −1.313 0.192 0.922 1.084
Baseline BMI −0.032 −0.102 −1.032 0.305 0.798 1.253
Baseline bone age −0.024 −0.087 −0.478 0.634 0.231 4.33
Baseline IGF-1 −0.002 −0.175 −1.569 0.12 0.62 1.612
Missed injection rate −5.017 −0.196 −2.005 0.048b 0.811 1.233
Group=long-acting group 0.149 0.158 1.537 0.128 0.731 1.369
Group=sequential group 0.158 0.15 1.502 0.136 0.769 1.3
F value 3.84a
Adjusted R2 0.197
D-W 2.1

  1. HtSDS, height standard deviation score; IGF-1, insulin-like growth factor 1; BMI, body mass index; VIF, variance inflation factor; B, unstandardized regression coefficient; β, standardized beta coefficient; D-W, Durbin–Watson. ap<0.01, bp<0.05.

Pharmacoeconomic analysis

Treatment cost comparison

The median total treatment costs after one year were ¥67,479.25 (60,261.43–85,774.80) for the LAGH group, ¥34,060.80 (29,291.10–39,940.90) for the SAGH group, and ¥64,730.90 (57,397.50–70,870.80) for the sequential therapy group. Kruskal–Wallis tests revealed significant between-group cost differences (H=11.79, p<0.01), and pairwise comparisons confirmed that the SAGH group incurred significantly lower costs than did either the LAGH group (Mann–Whitney U=34.0, p<0.01) or the sequential group (U=54.0, p<0.01) (Table 3). These findings identify the short-acting rhGH therapy regimen as the most cost-saving option among the three strategies.

Table 3:

Results of the cost-effectiveness analysis.

Group/metric Long-acting group (PEG-rhGH for 48 weeks) Short-acting group (rhGH for 48 weeks) Sequential group (PEG-rhGH for 24 weeks + rhGH for 24 weeks) Statistics, H
Cost, ¥ 67,479.25 (60,261.43–85,774.80) 34,060.80 (29,291.10–39,940.90) 64,730.90 (57,397.50–70,870.80) 11.79a
ΔHtSDS (efficacy) 1.02 0.85 1.20 68.89a
C/E Ratio (¥/ΔHtSDS) 67,403.70 (46,141.34–95,561.98) 42,181.15 (28,635.34–56,397.89) 52,278.11 (45,527.47–75,912.86) 15.35a
ICER (¥/ΔHtSDS) 196,579.06/1 unitb Reference 87,628.57/1 unitc –

  1. H, Kruskal–Wallis test statistic; C, cost; E, effectiveness; ΔHtSDS, change in the height standard deviation score; ICER, incremental cost-effectiveness. Data are presented as medians (interquartile ranges). ap<0.01. bICER for long-acting vs. short-acting: (67,479.25–34,060.80)/(1.02–0.85)=196,579.06. cICER for sequential vs. short-acting: (64,730.90–34,060.80)/(1.20–0.85)=87,628.57.

Cost-effectiveness analysis

The CEA employed two primary metrics: the cost-effectiveness ratio (C/E=total cost/ΔHtSDS) and the incremental cost-effectiveness ratio (ICER=[cost1 − cost0]/[ΔHtSDS1 − ΔHtSDS0]). The CEA revealed divergent outcomes. Whereas the long-acting group exhibited moderate efficacy (ΔHtSDS=1.02) and the short-acting group exhibited the lowest efficacy (ΔHtSDS=0.85), the sequential group reported the highest efficacy (ΔHtSDS=1.20). The cost-effectiveness ratio (C/E) varied significantly across the groups (H=15.35, p<0.001), in which context the short-acting group exhibited the lowest C/E (¥42,181.15 [28,635.34–56,397.89]), followed by the sequential group (¥52,278.11 [45,527.47–75,912.86]). The long-acting group exhibited the highest C/E (¥67,403.70 [46,141.34–95,561.98]). These findings suggest that the cost-effectiveness of the sequential regimen is intermediate in comparison with that of the other groups.

ICERs were calculated by using the SAGH group as the reference. The LAGH group required an additional ¥196,579.06 per ΔHtSDS unit gained (ICER=[67,479.25–34,060.80]/[1.02–0.85]), whereas the LAGH group needed only ¥87,628.57 per unit (p<0.01 for both vs. SAGH). Notably, compared with the LAGH regimen, the sequential strategy reduced the ICER by 55.4 %, thus indicating a more favourable trade-off between cost and efficacy in this context. The sequential regimen balanced efficacy (ΔHtSDS=1.20) with a cost (¥64,730.90) that was 90 % of the expenditure of the LAGH group. These data identify the sequential approach as a clinically viable alternative, which offers near-maximal growth outcomes at only a moderate financial burden (Table 3).

Safety assessment

No serious adverse events occurred in any treatment group; common reactions included injection site reactions, elevated blood glucose, and subclinical hypothyroidism, and no significant differences in incidence rates were observed (p>0.05).

Discussion

rhGH can improve height in cases of ISS, but issues with treatment compliance limit the efficacy of this approach. SAGH is less expensive but also leads to less adherence, whereas LAGH formulations improve compliance but entail higher costs. This study compared the efficacy, adherence, and cost-effectiveness of SAGH, LAGH, and sequential therapy in ISS children with the goal of providing guidance for clinical decisions in this context.

The LAGH regimen and sequential therapy outperform the SAGH regimen in terms of height changes and growth velocity, and they are associated with fewer missed injections; these results are in line with the findings of previous studies [18], 22]. However, after adjustments were made to account for confounding factors such as age, the missed injection rate was identified as the only significant predictor of treatment efficacy. Notably, all three regimens significantly improved height in children with ISS. The LAGH regimen resulted in the most pronounced improvement in adherence; however, the high costs of this treatment limit LAGH use, whereas sequential therapy offers efficacy and compliance alongside a reduced economic burden, thus exhibiting favourable cost-effectiveness.

Compared with the SAGH group (0.27 %), the LAGH and sequential therapy groups exhibited lower missed injection rates (0 and 0.27 %, respectively), thus indicating better compliance with LAGH therapy. The regression analysis revealed that missed injection rates negatively predict ΔHtSDS (β=−0.196, p<0.05), thus indicating that lower rates are linked to improved outcomes. These findings support the claims of previous studies that have reported that a 10 % increase in compliance increases the annual height velocity by 1.1 cm [23], [24], [25]. The sensitivity analysis revealed that, even after the missed injection rate in the long-acting growth hormone group was conservatively adjusted to 0.27 %, it remained a significant independent predictor of ΔHtSDS (β=−0.205, p=0.036). Although the ΔHtSDS and HV associated with the LAGH group and sequential therapy group were greater than those pertaining to the SAGH group, no significant differences were observed among the treatment regimens after adjustments were made to account for confounding factors in the regression analysis. These findings indicate that the baseline differences among the groups may be to the result of selection bias, which was taken into account in the regression analysis. Regardless of the treatment regimen used, efforts to maintain regular injections and reduce missed doses are crucial for ensuring effectiveness.

In addition to improving treatment adherence, a study conducted in Ireland [26] demonstrated that LAGH therapy is more cost-effective than SAGH therapy is. Compared with SAGH, LAGH formulations increased near-adult height (NAH) by an additional 1.87–3.66 cm, improved quality-adjusted life years (QALYs) by 0.21–0.50, and saved €5,699–21,974 per patient. Moreover, the cost per additional centimetre of height gain (€197–527) was lower for LAGH, thus indicating that the cost-effectiveness of this approach is superior to that of SAGH. However, in that study, the annual cost of LAGH was comparable to that of SAGH (€66,859 vs. €77,951), whereas in China’s current pricing structure, LAGH treatment costs significantly more per year than SAGH does (¥64,730.9 vs. ¥34,060.8). Although LAGH exhibited better efficacy (ΔHtSDS: 1.02 vs. 0.85), it was not significantly cost-effective in this context. In contrast, sequential therapy represents a more economically viable and clinically valuable option. This treatment costs ¥64,730 annually, thereby reducing expenses by 4.1 % compared with LAGH therapy while achieving similar height gains (ΔHtSDS: 1.20 vs. 1.02) and optimizing the ICER to ¥87,628.57, thus representing a 55 % reduction from the ¥196,579.06 associated with LAGH; accordingly, this approach can enhance accessibility in resource-limited settings.

Given that the treatment goal for ISS is height normalization and that the recommended intervention duration is at least two years [27], long-term economic sustainability is essential. Sequential therapy provides a new option for financially constrained populations, including middle- to low-income groups and even underinsured individuals in high-income healthcare systems. Additionally, given that growth hormone requires specialized storage conditions (4–8 °C) [28], LAGH formulations can help overcome the challenges of medication storage and administration for school-aged boarding students while simultaneously protecting patient privacy. The combined use of long-acting and short-acting growth hormone also offers a potential reference for efforts to develop new treatment strategies for this population.

No significant differences in ΔIGF-1 levels or bone age progression were observed across the groups, and no serious adverse events occurred, thus supporting the safety of sequential therapy. However, the following limitations warrant consideration [1]: A relatively small and unevenly distributed sample size (n=105) is an inherent feature of this retrospective, real-world study. Although we adjusted for known baseline covariates on the basis of multivariate statistical models and verified the stability of the primary outcome estimates through bootstrap resampling, the imbalanced sample size may still limit the statistical power of subgroup analyses or introduce unmeasured selection bias (e.g., socioeconomic disparities could have led to the overrepresentation of certain populations in specific treatment groups, thereby potentially inflating the adherence and efficacy outcomes). Sample size constraints (n=105) may limit the statistical robustness of this approach [2]. Although the adherence measurement, which was based on dispensed and returned medication records, was operationally convenient, it is nevertheless subject to information bias and may systematically overestimate true adherence. The degree of such overestimation likely varies by treatment regimen and is more pronounced in groups with lower injection frequency (e.g., long-acting formulations). The implausibly low missed injection rate (0 %) observed in the long-acting group is a manifestation of this methodological limitation and should be interpreted as the “upper limit of recordable adherence” according to the current method rather than indicating perfect adherence. A sensitivity analysis was conducted to assess the impact of this measurement error, and the results provided further support for the robustness of our core conclusion [3]. The 1-year follow-up period precluded the incorporation of quality-adjusted life years (QALYs) because of the inability of this research to capture long-term survival benefits for a sufficient duration to facilitate multidimensional health gain quantification; consequently, the CEA used ΔHtSDS as a natural outcome unit, which fails to provide a direct measure of QoL improvements. Future studies should aim to recruit larger, prospectively designed cohorts and use adherence monitoring tools that are more objective than self-reports, such as electronic monitoring. Additionally, such studies should implement preference-based instruments, such as the Child Health Utility 9D (CHU9D) [29], specifically to facilitate longitudinal QoL assessments. This combined approach could facilitate a cost-utility analysis (CUA) on the basis of QALYs, thereby providing a comprehensive evaluation of both survival and QoL impacts that can offer more robust economic evidence to support clinical decision-making.

In the context of treating ISS, sequential rhGH therapy represents a clinically and economically balanced approach. It ensures effective height gain and improved adherence while reducing overall costs. LAGH remains the preferred option when it is economically feasible; however, in budget-limited settings, SAGH may be a more suitable choice, despite its inherent limitations with respect to the maintenance of consistent treatment adherence. Future research should feature extended follow-up and integrate QALY assessments to refine the corresponding cost-benefit analyses.

Corresponding author: Liang Yan, Pediatric Genetic Metabolic Endocrinology, Tongji Hospital Affiliated to Huazhong University of Science and Technology, Wuhan, China, E-mail:
Li Jie and Li Bo contributed equally to this work.

Funding source: grant from the China International Medical Exchange Foundation

Award Identifier / Grant number: Grant No. Z-2019-41-2101-01

Acknowledgments

The authors thank the paediatric staff of Sichuan Provincial People’s Hospital for their assistance in data collection.

  1. Research ethics: This study was approved by the Institutional Review Board (IRB) of Sichuan Provincial People’s Hospital (Approval No. 2022-Lun-Shen (Research)-64-1). The study adhered to the principles of the Declaration of Helsinki and complied with local ethical regulations for retrospective research.

  2. Informed consent: Written informed consent was obtained from the parents or legal guardians of all participating children prior to enrolment.

  3. Author contributions: LJ, LB, and LY conceived and designed the study. LJ, LB, CLN, HL and CLB acquired the data. LJ and LY analysed and interpreted the data. LJ drafted the manuscript. LH, LY and LB critically revised the manuscript for important intellectual content. LY polished the manuscript and supervised the study. All authors have accepted responsibility for the entire content of this manuscript and approved its submission. JL is the guarantor.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: This study was supported by a grant from the China International Medical Exchange Foundation (Grant No. Z-2019-41-2101-01). The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.

  7. Data availability: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/jpem-2025-0573).

Received: 2025-10-07
Accepted: 2026-01-12
Published Online: 2026-01-28
Published in Print: 2026-03-26

© 2026 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Impact of eating behaviour on craniopharyngioma-associated obesity
  4. Original Articles
  5. Efficacy, adherence, and cost-efficiency of three growth hormone treatment strategies in children with idiopathic short stature: a retrospective cohort study
  6. Customized birth weight percentiles for identification of SGA short statue
  7. Suboptimal adoption of diabetes technology despite coverage and the impact on glycemic outcomes in children and adolescents with type 1 diabetes in Hong Kong
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  10. Efficacy and outcomes of 6-month triptorelin formulation in girls treated for central precocious puberty for 24 months and beyond
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  12. A rare metabolic cause of premature ovarian insufficiency: case report of transaldolase deficiency
  13. Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2
  14. Thyroid hormone metabolism defect due to compound heterozygous SECISBP2 mutations: first reported case in Korea
  15. The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment
  16. Rare phenotypic spectrum of 17β-hydroxysteroid dehydrogenase 3 deficiency: case series from infancy to adolescence
  17. Letters to the Editor
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https://doi.org/10.1515/jpem-2025-0573
Keywords for this article
growth hormone; therapeutic efficacy; treatment adherence; cost-effectiveness
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Impact of eating behaviour on craniopharyngioma-associated obesity
  4. Original Articles
  5. Efficacy, adherence, and cost-efficiency of three growth hormone treatment strategies in children with idiopathic short stature: a retrospective cohort study
  6. Customized birth weight percentiles for identification of SGA short statue
  7. Suboptimal adoption of diabetes technology despite coverage and the impact on glycemic outcomes in children and adolescents with type 1 diabetes in Hong Kong
  8. Impact of continuous glucose monitoring on fear of hypoglycemia and quality of life in children and adolescents with type 1 diabetes
  9. Evaluation of adrenomedullin levels in adolescents with Hashimoto’s thyroiditis: association with clinical and laboratory findings
  10. Efficacy and outcomes of 6-month triptorelin formulation in girls treated for central precocious puberty for 24 months and beyond
  11. Case Reports
  12. A rare metabolic cause of premature ovarian insufficiency: case report of transaldolase deficiency
  13. Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2
  14. Thyroid hormone metabolism defect due to compound heterozygous SECISBP2 mutations: first reported case in Korea
  15. The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment
  16. Rare phenotypic spectrum of 17β-hydroxysteroid dehydrogenase 3 deficiency: case series from infancy to adolescence
  17. Letters to the Editor
  18. Potential mechanistic role of the liver-thyroid axis in clinical manifestations of kwashiorkor
  19. Tolvaptan: a potential rescue therapy for SIADH with refractory hyponatremia associated with acute intermittent porphyria
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