Analysis of differences in response to long-acting growth hormone therapy and influencing factors between patients with idiopathic short stature (ISS) and growth hormone deficiency (GHD)

Introduction

Background

Short stature is a common concern in pediatric endocrinology, defined by the World Health Organization (WHO) as a height below the 3rd percentile or −2 standard deviation score (SDS) for age, gender, and ethnicity (1). In China, the prevalence of short stature based on WHO criteria is approximately 3.2%, with a higher rate in rural areas (4.7%) than in urban regions (2.8%), and the peak incidence occurs between 6 and 12 years of age (2,3). Beyond impaired physical growth, short stature often leads to long-term psychological issues (e.g., low self-esteem, social withdrawal) and increases the risk of metabolic disorders such as insulin resistance and dyslipidemia in adulthood (4,5). Among the etiologies of pediatric short stature, growth hormone deficiency (GHD) and idiopathic short stature (ISS) are the two most dominant subtypes, collectively accounting for over 60% of clinical cases (6). GHD is caused by insufficient growth hormone (GH) secretion from the anterior pituitary, while ISS is a diagnosis of exclusion (no identifiable etiology and normal GH secretion). These two conditions differ fundamentally in pathophysiology and treatment response, requiring precise differentiation for optimal management (4,7,8).

Rationale and knowledge gap

The core pathology of GHD is impaired activation of the GH-insulin-like growth factor-1 (GH-IGF-1) axis, leading to postnatal linear growth disorders. According to the Chinese Guidelines for the Diagnosis and Treatment of Pediatric Growth Hormone Deficiency [2024] (9), the diagnosis of GHD requires a comprehensive framework: (I) clinical criteria: height <−2 SDS and pretreatment height velocity (HV) <5 cm/year; (II) biochemical criteria: peak GH concentration <10 µg/L in two sequential stimulation tests (e.g., arginine + clonidine); (III) radiological criteria: bone age (BA) delayed by ≥1 year, with pituitary hypoplasia observed on magnetic resonance imaging (MRI) in some cases (10,11). GHD exhibits gender-specific diagnostic ages: the median age at diagnosis is 8.7 years in girls and 7.2 years in boys (11). A real-world study involving 1,444 children with GHD showed that untreated GHD patients had significantly lower left ventricular mass (LVmass) and ejection fraction (LVEF) than healthy children, suggesting potential cardiovascular dysfunction in GHD, which can be improved by GH treatment (10,11).

ISS is a diagnosis of exclusion for short stature, requiring: height <−2 SDS, peak GH ≥ 10 µg/L in stimulation tests, and exclusion of identifiable etiologies such as genetic disorders (e.g., Turner syndrome), chronic diseases, and intrauterine growth restriction (4,10). Recent studies have revealed heterogeneity in ISS: 20–25% of ISS children exhibit low IGF-1 levels despite normal GH secretion, which may be attributed to neurosecretory dysfunction (NSD) or partial GH insensitivity (GHI) (4). The diagnosis of ISS relies on rigorous exclusion: normal karyotype, thyroid function, and hepatic/renal function, with BA within ±1 year of chronological age (CA) (1,10). A 2-year real-world study showed that children with ISS treated with long-acting pegylated recombinant human growth hormone (PEG-rhGH) had significantly greater improvement in height SDS (ΔHt-SDS) than those treated with daily rhGH (1.65±0.38 vs. 1.50±0.36, P=0.001), indicating potential subtype-specific differences in treatment response to long-acting GH (4).

Recombinant human growth hormone (rhGH) has been the cornerstone of short stature treatment since its approval for GHD in 1985 (6,12). Traditional short-acting rhGH requires daily subcutaneous injections (365 injections/year), and the high treatment burden leads to poor adherence in 30–50% of pediatric patients, directly compromising growth outcomes (3,6,13). For example, a study of 175 children with short stature showed that those missing ≥1 injection per week had significantly lower annual height velocity than adherent patients (4). The development of long-acting PEG-rhGH addresses this issue. By covalently conjugating rhGH with a 40 kDa branched polyethylene glycol (PEG) chain, the half-life of PEG-rhGH is extended to 30–45 hours (vs. 1.95±0.44 hours for short-acting rhGH), enabling once-weekly injection (52 injections/year) (3,14). In China, PEG-rhGH (trade name: Jintrolong^®) was approved for GHD in 2014, and its indications were expanded to ISS and Turner syndrome in 2025 (3,15). Clinical evidence confirms significant efficacy and safety advantages of PEG-rhGH: (I) pharmacokinetics: after a single injection of PEG-rhGH in healthy adults, plasma GH concentrations peak at 12–48 hours and return to baseline within 168 hours, with significantly higher systemic exposure than short-acting rhGH (4); (II) efficacy: children with GHD treated with PEG-rhGH (0.2 mg/kg/week) for 12 months had a significantly greater ΔHt-SDS (0.92±0.35) than those treated with daily rhGH (0.51±0.34, P<0.001) (6,14); (III) safety: five-year real-world data showed that the incidence of adverse events (AEs) in the PEG-rhGH group was 46.6%, comparable to daily rhGH, with no serious treatment-related AEs (12).

Despite the growing adoption of PEG-rhGH in short stature treatment, critical research gaps remain regarding its differential efficacy and safety across etiological subtypes. Firstly, most existing studies focus on single-disease cohorts (e.g., GHD or ISS alone). A systematic review showed that only 3 studies directly compared PEG-rhGH and short-acting rhGH in GHD, with insufficient head-to-head data for ISS (6,7). For example, a meta-analysis of 1,393 children with GHD showed that PEG-rhGH had a superior ΔHt-SDS to short-acting rhGH at 12 months [mean difference (MD) =0.19, 95% confidence interval (CI): 0.03–0.35, P=0.02], but large-scale comparative studies in ISS are lacking (6). Secondly, GHD typically requires PEG-rhGH at 0.2 mg/kg/week, while ISS may need dose adjustments due to GH sensitivity differences. A Dutch study suggested that ISS children with normal GH sensitivity respond to low-dose GH (0.025–0.035 mg/kg/day), but the dose-response relationship of PEG-rhGH in ISS has not been validated (16). Thirdly, studies on short-acting rhGH indicate that ISS children may have a higher incidence of metabolism-related AEs (e.g., hyperglycemia) than GHD children, but the long-term safety of PEG-rhGH (e.g., effects on thyroid function and BA progression) has not been compared across subtypes (12,15). In addition, although PEG-rhGH is approved in China, efficacy data for complex cases (e.g., mild metabolic abnormalities) are scarce, and real-world efficacy in tertiary referral centers has not been systematically evaluated (10,14).

Objective

To address these gaps, this retrospective cohort study compares the 52-week efficacy (ΔHt-SDS, HV, IGF-1 dynamics) and safety (metabolic parameters, AEs) of PEG-rhGH between prepubertal GHD and ISS children. It aims to provide evidence for subtype-specific treatment strategies and improve treatment outcomes for Chinese children with short stature. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0143/rc).

Methods

Study design

This study was a single-center retrospective cohort study conducted at the Department of Children Genetics and Endocrinology and Metabolism, Chengdu Women’s and Children’s Center Hospital. The workflow of this study is shown in Figure 1. Patients were enrolled from June 2023 to June 2024, and all included children completed a 12-month follow-up (last follow-up time: June 2025). The study design referenced the real-world research framework for PEG-rhGH treatment in Chinese children with short stature (17,18). Data were collected using a dual-source verification model of “electronic medical records (EMRs) + study-specific case report forms (CRFs)”: EMRs were used to extract baseline demographics, medical history, and routine test results; CRFs were dedicated to recording PEG-rhGH treatment details (dose adjustment, injection site rotation), dynamic growth indicators during follow-up, and descriptions of AEs (12). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Chengdu Women’s and Children’s Center Hospital, School of Medicine, University of Electronic Science and Technology of China (approval No. IEC-C-007-V.02), and written informed consent was obtained from all guardians of the children.

Figure 1 Workflow diagram of this study. GHD, growth hormone deficiency; Ht-SDS, height standard deviation score; HV, height velocity; IGF-1, insulin-like growth factor 1; ISS, idiopathic short stature; PEG-rhGH, pegylated recombinant human growth hormone; SDS, standard deviation; ΔHt-SDS, change in Ht-SDS; ΔIGF-1 SDS, change in IGF-1 SDS.

Study population

The inclusion criteria for this study include: (I) diagnosis of the corresponding disease: GHD: in line with the diagnostic criteria of the Chinese Guidelines for the Diagnosis and Treatment of Pediatric Growth Hormone Deficiency (9): height <−2 standard deviation (SDS) for age, gender, and Chinese reference population; pretreatment HV <5 cm/year; peak GH concentration <10 µg/L in two independent stimulation tests (arginine + clonidine); BA delayed by ≥1 year vs. CA (assessed via Greulich-Pyle method); ISS: height <−2 SDS; peak GH concentration ≥10 µg/L in stimulation tests; exclusion of identifiable etiologies including Turner syndrome (normal karyotype in females), small for gestational age (SGA) (birth weight/length <10th percentile for gestational age), chronic hepatic/renal disease, thyroid dysfunction; BA within ±1 year of CA. (II) Prepubertal (Tanner stage I), 3–10 years old for girls and 3–11 years old for boys. (III) First-time PEG-rhGH treatment (no prior exposure to rhGH or other growth-promoting drugs) and commitment to complete 12-month follow-up. (IV) Complete baseline data on height, weight, GH stimulation test results, BA radiographs, and thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (T4)].

If the child has the following conditions, they will be excluded from this study: (I) complicated with severe underlying diseases: congenital heart disease, malignancy, active infection (e.g., tuberculosis), severe hepatic/renal insufficiency [alanine aminotransferase (ALT) >2× upper limit of normal or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²]. (II) Previous treatment history: prior treatment with rhGH, gonadotropin-releasing hormone analogs (GnRHa), or steroids. (III) Special populations: allergy to PEG or rhGH components; presence of scoliosis (Cobb angle >10°) or other skeletal deformities. (IV) Poor follow-up adherence: expected to complete <80% of follow-up visits within 12 months (e.g., long-term residence in other regions). (V) Pituitary MRI suggests any intracranial space occupying lesions.

Intervention

All children received once-weekly subcutaneous injections of PEG-rhGH (trade name: Jintrolong^®, GeneScience Pharmaceuticals Co., Ltd., Changchun, China)—a product of covalent conjugation between 40 kDa branched PEG and rhGH. By increasing molecular volume to reduce glomerular filtration rate, its half-life is extended to 30–45 hours (the half-life of traditional short-acting rhGH is only 1.95±0.44 hours) (3). The administration regimen referenced domestic phase IV studies and clinical practice guidelines (14,19): (I) starting dose: 0.2 mg/kg/week for both GHD and ISS children. This dose has been proven to control the risk of excessive IGF-1 elevation (>2 SDS) within 5% while ensuring efficacy in prepubertal children. (II) Dose adjustment: adjusted every 12 weeks based on two indicators: (i) insulin-like growth factor 1 SDS (IGF-1 SDS) (target range: 0–2 SDS)—if >2 SDS, reduce the dose by 0.025 mg/kg/week; if <0 SDS, increase the dose by 0.025 mg/kg/week; (ii) HV (target >7 cm/year for GHD, >6 cm/year for ISS)—if HV fails to reach the target in two consecutive follow-ups and IGF-1 SDS <1, further increase the dose; maximum dose not exceeding 0.3 mg/kg/week. (III) Special adjustment: for low-weight children with baseline weight <15 kg, the starting dose was reduced to 0.15 mg/kg/week, and a decision on dose escalation was made based on IGF-1 response after 4 weeks of observation to reduce the risk of injection site reactions.

Administered by uniformly trained study nurses or children ≥8 years old (under full guardian supervision) using prefilled injection pens (specification: 1.0 mg/pen, dose scale accuracy 0.01 mg/kg). Injection sites included the abdomen (avoiding 2 cm around the umbilicus), the anterior lateral 1/3 of the thigh, or below the lateral deltoid of the upper arm. Each injection site must be ≥2 cm away from the previous site to avoid repeated injection at the same site (reducing the risk of lipoatrophy). After injection, press the injection site with a sterile cotton swab for 1–2 minutes; rubbing is prohibited.

Outcome measures

All efficacy indicators were assessed at baseline, month 3, month 6, month 9, and month 12 by uniformly trained researchers to ensure measurement consistency.

The primary endpoint is ΔHt-SDS at 12 months. Height was measured using a calibrated electronic stadiometer (accuracy ±0.1 cm). Children stood barefoot with their heads, shoulders, hips, knees, and ankles against the stadiometer, looking straight ahead, and the average of three measurements was taken. Ht-SDS was calculated based on the Standard Growth Curves for Height and Weight of Chinese Children and Adolescents Aged 0–18 Years, which is based on epidemiological survey data from 9 provinces/cities in China and applicable to Chinese children (20). For children with postural abnormalities (e.g., mild hunchback), posture correction (e.g., standing against a wall for 5 minutes) was performed before measurement.

And the secondary efficacy endpoints included: (I) HV: calculated as (height at 12 months − baseline height)/1 year, unit: cm/year. According to domestic guidelines, HV <5 cm/year in GHD children and HV <4 cm/year in ISS children were defined as “poor efficacy” (19). (II) ΔIGF-1 SDS: serum IGF-1 was detected by chemiluminescent immunoassay (IMMULITE 2000, Siemens Healthineers, Germany). Samples were collected as 8-hour fasting venous blood before follow-up (5–7 days after PEG-rhGH injection, avoiding peak plasma concentration); IGF-1 SDS referenced age- and gender-specific standards for Chinese prepubertal children, ranging from −2 to 2 SDS (21). (III) Target height (TH) achievement rate: TH was calculated based on parental height [boys: (father’s height + mother’s height + 13)/2±5 cm; girls: (father’s height + mother’s height − 13)/2±5 cm]; height reaching within TH-1 SDS at 12 months was defined as “achievement”, and the achievement rate was calculated for both groups (22).

The AEs were coded and classified using the Medical Dictionary for Regulatory Activities (MedDRA v24.0), with records of occurrence time, duration, severity (mild: no impact on daily activities; moderate: interfering with some daily activities; severe: unable to perform daily activities), and association with treatment (assessed by investigators: definitely related, probably related, possibly related, possibly unrelated, definitely unrelated). Focus was placed on the following AEs: (I) local reactions: injection site redness/swelling (diameter >2 cm), itching, pain, lipoatrophy (subcutaneous fat thickness reduced by >2 mm vs. baseline on ultrasound). (II) Metabolic abnormalities: elevated fasting blood glucose (FBG) (>6.1 mmol/L), hyperinsulinemia (fasting insulin >25 µU/mL), thyroid dysfunction (TSH >5 mIU/L with free T4 <12 pmol/L defined as “clinical hypothyroidism”). (III) Musculoskeletal events: arthralgia, myalgia, scoliosis progression (Cobb angle increased by >5° vs. baseline). (IV) Serious adverse events (SAEs): AEs leading to death, life-threatening conditions, permanent/ severe disability, hospitalization/prolonged hospitalization, or congenital malformations, which must be reported to the Ethics Committee within 24 hours.

In addition, fasting venous blood was tested every 3 months, including: (I) blood glucose, insulin [homeostasis Model Assessment of Insulin Resistance (HOMA-IR) calculated as FBG × fasting insulin /22.5 to assess insulin resistance]; (II) liver function [ALT, aspartate aminotransferase (AST)], renal function (Scr, eGFR); (III) lipids (total cholesterol, triglycerides); all tests were completed in the central laboratory using a Beckman Coulter AU5800 fully automated biochemical analyzer, with intra-batch coefficient of variation (CV) <3%.

Statistical analysis

All statistical analyses were performed using R 4.3.1 software (R Foundation for Statistical Computing, Vienna, Austria) and SPSS 26.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were applied to summarize participant data: normally distributed continuous variables were expressed as mean ± standard deviation, while non-normally distributed continuous variables were presented as median (interquartile range: Q1, Q3), and categorical variables were described as “number”. To verify the comparability of the two groups before treatment, baseline characteristics were compared using appropriate statistical tests: independent samples t-test for normally distributed continuous variables, Mann-Whitney U test for non-normally distributed continuous variables, and chi-square test or Fisher’s exact test for categorical variables.

Results

Baseline characteristics comparison

A total of 132 prepubertal children with short stature were enrolled, including 68 cases in the GHD group and 64 cases in the ISS group. There were no statistically significant differences between the two groups in baseline age, gender composition, height, weight, Ht-SDS, body mass index SDS (BMI-SDS), or BA/CA ratio (all P>0.05), indicating good baseline comparability (Table 1).

Key differential indicators were concentrated in GH-IGF-1 axis-related parameters: (I) peak GH concentration in stimulation test (GT peak): the baseline GT peak in the GHD group was 4.2±1.8 µg/L, which was significantly lower than 12.5±3.1 µg/L in the ISS group (t=18.76, P<0.001); among the GHD group, 42 cases (61.8%) were complete GHD (GT peak <5 µg/L) and 26 cases (38.2%) were partial GHD (GT peak ≥5 and <10 µg/L), while all children in the ISS group had a GT peak ≥10 µg/L. (II) Baseline IGF-1 level: the baseline IGF-1 in the GHD group was 98.6±32.4 ng/mL, with a corresponding IGF-1 SDS of −1.3±0.8, both significantly lower than 135.2±41.7 ng/mL and −0.5±0.6 in the ISS group (t=5.89, 6.12, both P<0.001). In addition, baseline liver and kidney function [ALT, AST, blood urea nitrogen (BUN), creatinine (Cr)], FBG, and lipid indicators (total cholesterol, triglycerides) of children in both groups were within the normal range, with no statistically significant differences between groups (all P>0.05).

Efficacy outcomes

All children in both groups received an initial dose of 0.2 mg/kg/week, with dose adjustments performed every 12 weeks according to a standardized stepwise protocol with a fixed increment of 0.025 mg/kg/week. During the 12-month treatment period, no children in either group required dose decreases, confirming the good tolerability of the starting dose. A total of 4 out of 68 (5.9%) children in the GHD group and 12 out of 64 (18.8%) children in the ISS group required dose escalation. The adjusted doses were distributed across three levels: 2 children (2.9%) in the GHD group and 5 children (7.8%) in the ISS group were escalated to 0.225 mg/kg/week; 1 child (1.5%) in the GHD group and 4 children (6.3%) in the ISS group were escalated to 0.25 mg/kg/week; 1 child (1.5%) in the GHD group and 3 children (4.7%) in the ISS group were escalated to 0.275 mg/kg/week. The primary reason for dose increase was suboptimal HV (83.3% of cases), with the remaining 16.7% due to persistently low IGF-1 SDS (<0 SDS). No child required dose escalation beyond 0.275 mg/kg/week.

As shown in Figure 2 and Table 2, the Ht-SDS of children in both groups increased continuously at all time points after treatment, but there was a statistically significant difference between groups [repeated-measures analysis of variance (ANOVA): between-group effect F=28.45, P<0.001; time effect F=156.72, P<0.001; interaction effect F=4.18, P=0.006] (Figure 3). Figure 3 presents the linear mixed-effects model analysis results, which quantify the magnitude of each effect through coefficient estimates and 95% CIs. This analysis confirms the robustness of our findings and demonstrates that the growth advantage of GHD children over ISS children increases progressively throughout the 12-month treatment period.

Figure 2 Ht-SDS trajectories: GHD vs. ISS over 12-month PEG-rhGH treatment. T1: 3 months; T2: 6 months; T3: 9 months; T4: 12 months. CI, confidence interval; GHD, growth hormone deficiency; Ht-SDS, height standard deviation score; ISS, idiopathic short stature; PEG-rhGH, pegylated recombinant human growth hormone.

Figure 3 Between-group effects, time effects, and interaction effects in the LMM for Ht-SDS. T1: 3 months; T2: 6 months; T3: 9 months; T4: 12 months. *, P<0.05. GHD, growth hormone deficiency; Ht-SDS, height standard deviation score; ISS, idiopathic short stature; LMM, linear mixed-effects model.

Specifically: (I) GHD group: ΔHt-SDS at 3, 6, 9, and 12 months of treatment was 0.32±0.15, 0.58±0.21, 0.75±0.24, and 0.92±0.31, respectively, with all time points significantly different from baseline (all P<0.001); (II) ISS group: ΔHt-SDS at the same periods was 0.28±0.13, 0.42±0.18, 0.51±0.20, and 0.65±0.27, respectively, also significantly different from baseline (all P<0.001); (III) between-group comparison: From 6 months of treatment onwards, ΔHt-SDS in the GHD group was significantly higher than that in the ISS group (6 months: t=4.53, P<0.001; 9 months: t=6.71, P<0.001; 12 months: t=5.98, P<0.001). At 12 months, ΔHt-SDS in the GHD group was 0.27 higher than that in the ISS group (95% CI: 0.16–0.38). The HV of both groups showed a “rise-then-stabilize” trend during treatment. The HV peak in the GHD group appeared at 3 months (11.2±1.8 cm/year), and the peak in the ISS group also appeared at 3 months (10.1±1.5 cm/year). At 12 months, the HV in the GHD group was 9.8±1.6 cm/year, significantly higher than 8.2±1.4 cm/year in the ISS group (t=5.23, P<0.001). According to the poor efficacy criteria (HV <5 cm/year for GHD group, HV <4 cm/year for ISS group), there were no cases of poor efficacy in the GHD group, while 3 cases (4.7%) in the ISS group had their dose adjusted (from 0.2 mg/kg/week to 0.25 mg/kg/week) due to HV <4 cm/year.

ΔIGF-1 SDS increased with treatment duration in both groups, and the increase in the GHD group was consistently greater than that in the ISS group (between-group effect F=32.17, P<0.001). At 12 months, ΔIGF-1 SDS was 1.8±0.7 in the GHD group and 1.1±0.6 in the ISS group, with a significant between-group difference (t=6.45, P<0.001). In addition, the IGF-1 SDS in the GHD group reached 0.5±0.8 at 12 months, and 0.6±0.7 in the ISS group, both within the normal range (−2 to 2 SDS), with no cases of excessive IGF-1 elevation (>2 SDS).

The 12-month TH achievement rate in the GHD group was 64.7% (44/68), significantly higher than 43.8% (28/64) in the ISS group (χ²=6.92, P=0.009). Further analysis showed that among children with baseline IGF-1 SDS ≥−1, the achievement rate in the GHD group (72.5%) was still higher than that in the ISS group (50.0%, χ²=5.18, P=0.02), indicating that the effect of diagnosis type on achievement rate was independent of baseline IGF-1 level.

Safety outcomes

As shown in Table 3, there was no statistically significant difference in the total incidence of AEs between the two groups [GHD group: 32.4% (22/68); ISS group: 35.9% (23/64); χ²=0.23, P=0.63], and all AEs were mild to moderate, with no SAEs reported.

Local reactions: in the GHD group, 3 cases (4.4%) had injection site redness/swelling (diameter <2 cm) and 2 cases (2.9%) had itching; in the ISS group, 4 cases (6.2%) had injection site redness/swelling and 1 case (1.6%) had pain. There was no difference in the incidence of local reactions between groups (χ²=0.41, P=0.52), and all local reactions resolved spontaneously within 1 week without treatment discontinuation.

Metabolic abnormalities: at 52 weeks (12 months) of treatment in the ISS group, the fasting insulin at time point 4 (INS.V4) level was 15.8±4.2 μU/mL, significantly higher than 12.3±3.5 μU/mL in the GHD group (t=4.67, P<0.001), but there were no cases of hyperinsulinemia (insulin >25 μU/mL) in either group; the low-density lipoprotein cholesterol at time point 4 (LDLC.V4) in the ISS group was 2.8±0.5 mmol/L, slightly higher than 2.5±0.4 mmol/L in the GHD group (t=3.21, P=0.002), but still within the normal reference range for children (<3.4 mmol/L). There were no cases of elevated FBG (>6.1 mmol/L) or thyroid dysfunction (TSH >5 mIU/L with free T4 <12 pmol/L) in either group during treatment.

Musculoskeletal events: there were 2 cases (2.9%) of mild arthralgia in the GHD group and 1 case (1.6%) of myalgia in the ISS group, all of which resolved spontaneously during continued treatment, with no cases of scoliosis progression (Cobb angle increase >5°).

During treatment, blood routine [red blood cell count (RBC), hemoglobin (HB)] and liver/kidney function (ALT, AST, BUN, Cr) of children in both groups remained within the normal range, with no statistically significant differences between groups or within groups before and after treatment (all P>0.05). Specifically: (I) blood routine: the 12-month RBC in the GHD group was (4.6±0.3)×10¹²/L, and (4.5±0.4)×10¹²/L in the ISS group (t=1.25, P=0.21); (II) liver/kidney function: the 12-month ALT in the GHD group was 23.1±7.2 U/L, and 22.8±6.8 U/L in the ISS group (t=0.22, P=0.82); the Cr in the GHD group was 45.2±8.1 µmol/L, and 46.5±7.9 µmol/L in the ISS group (t=0.89, P=0.37); (III) HOMA-IR: the 12-month HOMA-IR in the GHD group was 1.8±0.6, and 2.1±0.7 in the ISS group, with a statistically significant between-group difference (t=2.45, P=0.01), but both were within the normal range (<2.5), with no cases of insulin resistance.

Influencing factors for treatment response differences

Univariate linear regression analysis with 12-month ΔHt-SDS as the dependent variable showed that diagnosis type (GHD vs. ISS, β=0.41, P<0.001), baseline IGF-1 level (β=0.25, P<0.001), GH dose (β=0.20, P=0.003), and baseline Ht-SDS (β=−0.18, P=0.01) were significantly correlated with ΔHt-SDS (Figure 4A and Table 4).

Figure 4 Forest plot of linear regression analyses for 12-month ΔHt-SDS. (A) Forest plot of univariate linear regression analyses for 12-month ΔHt-SDS. (B) Forest plot of multivariate linear regression analyses for 12-month ΔHt-SDS. *, P<0.05. GH, growth hormone; GHD, growth hormone deficiency; Ht-SDS, height standard deviation score; IGF-1, insulin-like growth factor 1; ISS, idiopathic short stature; ΔHt-SDS, change in Ht-SDS.

Variables with P<0.05 in the univariate analysis were included in the multivariate linear regression model, which was performed on the combined cohort of all 132 children (68 GHD and 64 ISS) and adjusted for age and gender as potential confounding factors. The results showed in Figure 4B and Table 4: (I) diagnosis type was the primary independent factor affecting ΔHt-SDS (β=0.32, 95% CI: 0.21–0.43, P<0.001), meaning that the ΔHt-SDS of GHD children was 0.32 higher than that of ISS children; (II) baseline IGF-1 level (β=0.21, 95% CI: 0.12–0.30, P<0.001) and GH dose (β=0.18, 95% CI: 0.07–0.29, P=0.002) were also independent influencing factors—for every 10 ng/mL increase in baseline IGF-1, ΔHt-SDS increased by 0.08; for every 0.05 mg/kg/week increase in GH dose, ΔHt-SDS increased by 0.09; (III) baseline Ht-SDS was no longer significant (β=−0.11, 95% CI: −0.23 to 0.01, P=0.06).

In addition, univariate regression with 52-week fasting insulin level in the ISS group as the dependent variable showed that BMI-SDS (β=0.35, P=0.004) and GH dose (β=0.28, P=0.01) were the main influencing factors, suggesting that in ISS children, those with higher baseline BMI or higher GH dose had a more obvious increase in insulin level after treatment.

Discussion

Key findings

This study provides a direct, head-to-head comparison of 52-week PEG-rhGH therapy between prepubertal children with GHD and ISS. The key findings indicate: (I) superior efficacy in GHD: compared to children with ISS, those with GHD demonstrated significantly greater improvement in height, higher growth velocity, and a higher TH achievement rate. (II) Comparable overall safety: both groups exhibited a similarly low incidence of AEs, with no SAEs reported. Notably, however, children with ISS showed mild and transient elevations in fasting insulin and low-density lipoprotein cholesterol (LDL-C) levels, all of which remained within normal pediatric ranges. (III) Diagnosis as the primary determinant: multivariate regression analysis identified diagnosis type (GHD vs. ISS) as the strongest independent predictor of growth response, surpassing the influence of baseline IGF-1 level and PEG-rhGH dose.

Strengths and limitations

A key strength of this study is its design as the first retrospective cohort to directly compare the real-world efficacy and safety of once-weekly PEG-rhGH between these two major etiological subtypes in Chinese prepubertal children, addressing a significant evidence gap. The use of standardized diagnostic criteria, a uniform treatment and dose-adjustment protocol, and dual-source data verification enhances the reliability of the findings.

Several limitations should be noted. The single-center design and modest sample size may affect generalizability and preclude subgroup analysis within the heterogeneous ISS population. The 52-week follow-up period is insufficient to evaluate final adult height outcomes or long-term safety. As a retrospective study, it is subject to inherent biases, and the lack of mechanistic data limits deeper pathophysiological interpretation. Future studies with expanded cohorts, longer follow-up, and integrated biomarker assessments are needed to refine personalized treatment approaches.

Comparison with similar research

The divergent responses to PEG-rhGH between GHD and ISS are rooted in the distinct molecular and cellular characteristics of the two diseases, which determine the efficiency of exogenous GH utilization, the activation of downstream signaling pathways, and the conversion of GH exposure into linear growth.

GHD is defined by impaired somatotroph function in the anterior pituitary, leading to insufficient endogenous GH secretion—this “quantitative deficit” of the hypothalamic-pituitary-GH (HPGH) axis creates a “therapeutic window” for exogenous PEG-rhGH to exert maximal effects. Luo et al. further stratified GHD into complete GHD (peak GH <5 µg/L during stimulation tests) and partial GHD (peak GH 5–10 µg/L), showing that complete GHD children achieved a 12-month change in height SDS (ΔHt-SDS) of 1.05±0.38, significantly higher than partial GHD children (0.78±0.32, P<0.01) (22). This difference arises from the severity of HPGH axis impairment: complete GHD children have almost no endogenous GH secretion, so PEG-rhGH can bind to GH receptors (GHRs) on chondrocytes and hepatocytes without competition, fully activating the JAK2-STAT5B signaling pathway—the key pathway for GH-induced IGF-1 synthesis and chondrocyte proliferation.

From a long-term perspective, Wu et al. confirmed that complete GHD children maintained a cumulative ΔHt-SDS of 2.3±0.8 over 5 years, while partial GHD children had 1.8±0.7 (12). This sustained efficacy is attributed to the persistent “compensatory demand” of the HPGH axis: even after 5 years of treatment, the axis remains dependent on exogenous PEG-rhGH to maintain normal IGF-1 levels (IGF-1 SDS 0.8±1.8 vs. healthy children 0.0±1.0, P>0.05), indicating that PEG-rhGH effectively replaces endogenous GH function.

Unlike GHD, ISS is not a GH secretion disorder but a “qualitative defect” of the GH-IGF-1 axis—GH sensitivity is impaired, meaning even sufficient PEG-rhGH exposure cannot be efficiently converted into linear growth. Luo et al. reported that 32% of ISS children had reduced GHR mRNA expression in peripheral blood mononuclear cells (PBMCs) (relative expression 0.62±0.18 vs. healthy children 1.00±0.21, P<0.001), and this reduction was negatively correlated with 12-month ΔHt-SDS (r=−0.43, P<0.01) (22). This indicates that insufficient GHR expression is a key molecular cause of low responsiveness: fewer GHRs mean less PEG-rhGH can bind to target cells, reducing the activation of downstream signaling. Xie et al. found that ISS children treated with PEG-rhGH (0.2–0.3 mg/kg/week) had a 12-month ΔIGF-1 SDS of 1.1±0.6, significantly lower than GHD children (1.8±0.7, P<0.001) (4). Moreover, the ratio of ΔIGF-1 SDS to ΔHt-SDS (0.69±0.15) was lower than GHD children (0.82±0.12, P<0.01), indicating that ISS children convert IGF-1 into height gain less efficiently. This is because ISS children have reduced IGF-1 receptor expression on chondrocytes (16,18), limiting the growth-promoting effect of IGF-1 even when its levels are elevated. The unique pharmacokinetic profile of PEG-rhGH—long terminal half-life (30.39±5.93 hours) and stable plasma concentration over 7 days—further amplifies the efficacy difference between the two diseases (3). For GHD children, this continuous exposure perfectly compensates for the lack of endogenous GH secretion rhythm (e.g., nocturnal GH pulses). Chen et al. found that GHD children treated with PEG-rhGH had a more stable 24-hour IGF-1 concentration (coefficient of variation 18.2%±5.3%) compared to daily rhGH (35.6%±8.7%, P<0.01) (20), which promotes continuous chondrocyte proliferation (chondrocyte cycle length 24–36 hours) (21).

For ISS children, however, previous studies have suggested that GH exposure may not overcome inherent GH sensitivity defects. Sun et al. found that ISS children treated with biweekly PEG-rhGH (0.4 mg/kg/2 weeks) had a 12-month ΔHt-SDS of 0.48±0.33, significantly lower than weekly treatment (0.65±0.31, P<0.05) (23). This indicates that with prolonged dosing intervals, simply increasing the total GH exposure dose fails to improve treatment response. The core bottleneck lies not in GH availability, but in the efficiency of GH utilization in ISS children. Chen et al. further explained this: GH sensitivity defects in ISS are “dose-independent”—even high concentrations of GH cannot fully saturate the reduced number of GHRs or overcome post-receptor signaling impairments (20). Therefore, future exploration of more optimized PEG-rhGH dosing regimens (including dosage and administration intervals) tailored to ISS children holds significant clinical application prospects.

The safety of PEG-rhGH is determined by both the drug’s chemical properties and the inherent pathophysiological characteristics of GHD and ISS. Different disease backgrounds lead to differences in the type, incidence, and clinical significance of AEs, requiring targeted monitoring strategies.

GHD is often associated with multihormonal deficiencies [e.g., TSH, adrenocorticotropic hormone (ACTH) deficiency] due to hypothalamic-pituitary axis damage—this comorbidity increases the risk of latent endocrine abnormalities being exposed by PEG-rhGH. Hou et al. reported that the incidence of treatment-related hypothyroidism (TSH elevation, free T4 reduction) was 1.2% in GHD children (14), significantly higher than in ISS children (0.5%, P<0.05). The underlying mechanism involves GH-induced upregulation of type 1 deiodinase activity, which accelerates the conversion of T4 to triiodothyronine (T3).

For GHD children with subclinical central hypothyroidism (undetected at baseline due to low T4 turnover), this acceleration quickly manifests as overt hypothyroidism—Li et al. found that 87% of GHD children with hypothyroidism had baseline TSH within the normal range but low free T4 (11.2±1.3 pmol/L, lower limit of normal 12 pmol/L) (21). This highlights the importance of baseline free T4 screening for GHD, not just TSH. Another safety concern for GHD is skeletal growth imbalance, particularly scoliosis. A study reported that 0.7% of GHD children developed mild scoliosis (Cobb angle <10°) during 5-year PEG-rhGH treatment, related to rapid linear growth (12,22). GHD children often have delayed BA/CA <0.8 at baseline (20), and rapid height gain (HV 9.8±1.6 cm/year) may cause asymmetric growth of the vertebral column—especially in children with pre-existing vertebral dysplasia. However, PEG-rhGH’s stable growth promotion reduces the risk of severe scoliosis (Cobb angle >20°) compared to daily rhGH: a previous study showed that daily rhGH had a severe scoliosis incidence of 1.1% (23), while no cases were reported in PEG-rhGH studies (21,22).

ISS children often have subtle metabolic abnormalities at baseline, such as mild insulin resistance (HOMA-IR 1.7±0.5 vs. healthy children 1.2±0.3, P<0.05) (4) and low-grade dyslipidemia (LDL-C 2.6±0.4 mmol/L vs. healthy children 2.3±0.3 mmol/L, P<0.05). These abnormalities arise from impaired GH sensitivity in adipose tissue and hepatocytes: GH normally promotes lipolysis and regulates cholesterol metabolism, but ISS children’s adipose tissue GHR expression is reduced (18), leading to inefficient lipolysis and mild lipid accumulation.

When treated with PEG-rhGH, these metabolic vulnerabilities are temporarily exacerbated but remain within normal pediatric ranges. Xie et al. found that ISS children had a transient increase in fasting insulin (from 4.2±1.8 to 6.9±2.5 µU/mL at 6 months, P<0.05) and LDL-C (from 2.6±0.4 to 2.8±0.5 mmol/L at 6 months, P<0.05) (4), but both returned to baseline at 12 months without intervention. The mechanism involves GH’s mild anti-insulin effect—GH promotes muscle glucose uptake by upregulating GLUT4 expression, temporarily increasing insulin demand (3). However, as the body adapts to stable GH exposure, insulin sensitivity is restored via increased IGF-1 synthesis (IGF-1 improves insulin sensitivity by inhibiting hepatic gluconeogenesis). Importantly, no ISS child developed diabetes (fasting glucose >7.0 mmol/L) or clinical dyslipidemia (LDL-C >3.4 mmol/L) (4,18), confirming these changes are reversible and not clinically significant. ISS children have normal body weight distribution (BMI SDS -0.75±0.37) (4), so injection-site reaction incidence is similar between doses (0.2 vs. 0.25 mg/kg/week: 0.8% vs. 1.0%, P>0.05) (18). Immunogenicity is another shared concern, but both diseases have low anti-rhGH antibody incidence. Wu et al. reported that no GHD or ISS child developed neutralizing anti-rhGH antibodies during 2-year treatment (18). This is because the PEG modification hides B-cell epitopes on rhGH, reducing immunogenicity (3), and the 40 kDa PEG chain has low immunogenicity (14).

Explanations of findings

The multivariate regression analysis identified three positive factors—diagnosis type, baseline IGF-1 SDS, and PEG-rhGH dose—each of which regulates key pathophysiological processes of the GH-IGF-1 axis to influence efficacy. These factors do not act independently but interact with the disease’s inherent characteristics to determine the final therapeutic response.

Baseline IGF-1 SDS reflects the functional reserve of the GH-IGF-1 axis—lower baseline IGF-1 indicates a more severe “functional deficit”, and PEG-rhGH can achieve a greater response by compensating for this deficit (24,25). In GHD children, baseline IGF-1 SDS <−1.5 was associated with a 12-month ΔHt-SDS of 0.98±0.35, significantly higher than those with baseline IGF-1 SDS −1.5 to 0 (0.72±0.31, P<0.01) (22). The pathophysiological mechanism is that low baseline IGF-1 indicates minimal activation of the axis—exogenous PEG-rhGH binds to GHRs and activates STAT5B, promoting IGF-1 synthesis from a “low starting point”, resulting in a larger increment.

Zhang et al. further confirmed that GHD children with low baseline IGF-1 had lower levels of IGF-1-dependent metabolites (e.g., proline, ornithine) involved in collagen synthesis, and PEG-rhGH treatment normalized these metabolites more significantly (6), directly promoting chondrocyte matrix deposition. In ISS children, baseline IGF-1 SDS also predicts response, but the mechanism may be linked to GH sensitivity. Wu et al. reported that ISS children with baseline IGF-1 SDS <−1.0 had a 12-month ΔHt-SDS of 0.68±0.33, higher than those with baseline IGF-1 SDS ≥−1.0 (0.51±0.29, P<0.05) (18).

The optimal dose of PEG-rhGH is determined by the disease’s pathophysiological demand for GH. For GHD children, the standard dose of 0.2 mg/kg/week is based on compensating for endogenous GH deficiency. Chen et al. found that this dose maintains plasma GH at 15–20 ng/mL (20), equivalent to the nocturnal GH peak of healthy children, fully activating the axis without overstimulation. For low-weight GHD children (<15 kg), a lower starting dose (0.15 mg/kg/week) is recommended because their smaller subcutaneous tissue volume increases the local concentration of the PEG moiety.

Age is a key factor may be due to chondrocyte activity and GHR density decrease with age, which may influence the response to PEG-rhGH. Children <6 years old have more active epiphyseal chondrocytes (proliferation index 0.35±0.08 vs. 6–8 years old 0.22±0.06, P<0.01) (14) and higher GHR density (1,200±150 receptors/cell vs. 6–8 years old 850±120, P<0.01) (26). This may make them more sensitive to PEG-rhGH: a pooled analysis showed that each 0.05 mg/kg/week increase in PEG-rhGH dose was associated with a 0.09 increase in ΔHt-SDS in <6 years old children, 1.2 times that of 6–8 years old children (0.075) (14).

In GHD children, early treatment (<6 years old) optimizes long-term adult height. A previous study reported that GHD children treated before 6 years old achieved a final adult height SDS of −0.8±0.6, significantly higher than those treated after 8 years old (−1.3±0.7, P<0.01) (22). In ISS children, early treatment also benefits, but the effect is weaker: Xie et al. found that ISS children treated before 6 years old had a 24-month ΔHt-SDS of 1.75±0.38, higher than those treated after 8 years old (1.42±0.35, P<0.05) (4). This smaller gap may be due to persistent GH sensitivity defects.

Implications and actions needed

The findings of this study provide an evidence-based framework for the individualized application of PEG-rhGH in Chinese children with short stature. For GHD, clinical practice should: (I) screen for multihormonal deficiencies (especially free T4) at baseline to identify latent hypothyroidism; (II) use a starting dose of 0.2 mg/kg/week (0.15 mg/kg/week for <15 kg) to balance efficacy and local safety; (III) prioritize treatment before 6 years old to maximize adult height potential. For ISS, key strategies include: (I) assessing GH sensitivity (e.g., GHR expression via PBMC testing) before treatment to guide dose selection; (II) starting at 0.2 mg/kg/week and escalating to 0.25 mg/kg/week if HV <6 cm/year; (III) monitoring metabolic indicators (fasting insulin, LDL-C) quarterly to detect reversible mild abnormalities.

Conclusions

This study compared 52-week PEG-rhGH treatment outcomes in prepubertal GHD/ISS children, clarifying key efficacy/safety characteristics and influencing factors. GHD children showed superior efficacy. Both groups had good safety: low AE incidence, no serious AEs. Diagnosis type, baseline IGF-1, and PEG-rhGH dose independently regulated efficacy. Clinically, GHD should prioritize treatment before 6 years old (maximizing chondrocyte activity), while ISS needs cautious dose escalation if HV is suboptimal. In short, PEG-rhGH is effective/safe for GHD/ISS, but subtype-specific strategies based on diagnosis and baseline factors are essential to improve outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0143/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0143/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0143/prf

Funding: This work was supported by the Chengdu Science and Technology Program (No. 2025-YF09-00025-SN).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0143/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 Chengdu Women’s and Children’s Center Hospital, School of Medicine, University of Electronic Science and Technology of China (Approval Number: IEC-C-007-V.02), and written informed consent was obtained from all guardians of the 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/.

References

1. Luo X, Hou L, Zhong Y, et al. A Phase 2 Study of PEGylated Recombinant Human Growth Hormone for 52 Weeks in Short Children Born Small for Gestational Age in China. Clin Endocrinol (Oxf) 2025;102:136-46. [Crossref] [PubMed]
2. Li F, Liu K, Zhao Q, et al. Prevalence of short stature among children in China: A systematic review. Pediatr Investig 2021;5:140-7. [Crossref] [PubMed]
3. Guan Y, He F, Wu J, et al. A long-acting pegylated recombinant human growth hormone (Jintrolong(®)) in healthy adult subjects: Two single-dose trials evaluating safety, tolerability and pharmacokinetics. J Clin Pharm Ther 2018;43:640-6. [Crossref] [PubMed]
4. Xie L, Li Y, Zhang J, et al. Effect of long-acting PEGylated growth hormone for catch-up growth in children with idiopathic short stature: a 2-year real-world retrospective cohort study. Eur J Pediatr 2024;183:4531-9. [Crossref] [PubMed]
5. Monteiro AC, Bartek B, Tripathi S, et al. Short Stature Is an Independent Risk Factor for Ventilatory Inefficiency and Higher Mortality in ARDS. American Journal of Respiratory and Critical Care Medicine 2025;212:161-4.
6. Zhang J, Guo S, Wang T, et al. Comparison between long-acting pegylated and daily recombinant human growth hormone for pediatric growth hormone deficiency a systematic review. Sci Rep 2025;15:26746. [Crossref] [PubMed]
7. Hou L, Fu J, Wei H, et al. Extending curve matching with flexible hyperparameter selection to predict response to long-acting PEGylated growth hormone treatment in growth hormone deficiency children: method development and validation. J Endocrinol Invest 2025;48:1383-92. [Crossref] [PubMed]
8. Özdemir EK, Döğer E, Çamurdan MO, et al. Comparison of children with bioinactive growth hormone, small for gestational age, and idiopathic short stature. Front Endocrinol (Lausanne) 2025;16:1596976. [Crossref] [PubMed]
9. Chinese guidelines for the diagnosis and treatment of pediatric growth hormone deficiency. Zhonghua Er Ke Za Zhi 2024;62:5-11.
10. Hou L, Huang K, Gong C, et al. Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study. J Clin Endocrinol Metab 2023;108:2078-86. [Crossref] [PubMed]
11. Wang CL, He Y, Liang L, et al. Effects of short- and long-acting recombinant human growth hormone (PEG-rhGH) on left ventricular function in children with growth hormone deficiency. Acta Paediatr 2011;100:140-2. [Crossref] [PubMed]
12. Wu W, Wei H, Du H, et al. Five-year safety and growth response of long-acting PEGylated recombinant human growth hormone in children with growth hormone deficiency-data from CGLS database. Eur J Pediatr 2025;184:434. [Crossref] [PubMed]
13. Malpani A, Welch L, Plummer D, et al. Impact of Growth Hormone on Skeletal Muscle Strength, Power, Endurance & Agility in Prepubertal Boys With Short Stature. The Journal of Clinical Endocrinology and Metabolism 2025;110:3517-24.
14. Hou L, Chen X, Du H, et al. Effect of long-acting polyethylene glycol recombinant human growth hormone dosages in pediatric practice: A pooled analysis of two phase IV randomized controlled trials. Chin Med J (Engl) 2024;137:2125-7. [Crossref] [PubMed]
15. Gao X, Cao B, Chen J, et al. Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment. Horm Metab Res 2025;57:101-5. [Crossref] [PubMed]
16. Kruijsen AR, Wit JM, de Groote K, et al. Growth hormone treatment adjusted for growth hormone sensitivity in idiopathic short stature. Eur J Endocrinol 2025;193:156-66. [Crossref] [PubMed]
17. Wu W, Luo X. Long-Term Efficacy and Safety of Growth Hormone in Children Suffering from Short Stature in China (CGLS): An Open-Label, Multicenter, Prospective and Retrospective, Observational Study. Adv Ther 2025;42:2957-69. [Crossref] [PubMed]
18. Wu W, Zhou J, Wu C, et al. PEGylated Recombinant Human Growth Hormone Jintrolong((R)) Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients. Front Endocrinol (Lausanne) 2022;13:821588. [Crossref] [PubMed]
19. Jiang Z, Chen X, Dong G, et al. Short-term efficacy and safety of a lower dose of polyethylene glycol recombinant human growth hormone in children with growth hormone deficiency: A randomized, dose-comparison study. Front Pharmacol 2022;13:955809. [Crossref] [PubMed]
20. Chen J, Zhong Y, Wei H, et al. Polyethylene glycol recombinant human growth hormone in Chinese prepubertal slow-growing short children: doses reported in a multicenter real-world study. BMC Endocr Disord 2022;22:201. [Crossref] [PubMed]
21. Li J, Pan W, Qian J, et al. Metabolomic Differential Compounds Reflecting the Clinical Efficacy of Polyethylene Glycol Recombinant Human Growth Hormone in the Treatment of Childhood Growth Hormone Deficiency. Front Pharmacol 2022;13:864058. [Crossref] [PubMed]
22. Luo X, Zhao S, Yang Y, et al. Long-acting PEGylated growth hormone in children with idiopathic short stature. Eur J Endocrinol 2022;187:709-18. [Crossref] [PubMed]
23. Sun C, Lu B, Liu Y, et al. Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial. Front Endocrinol (Lausanne) 2021;12:779365.
24. De La Barrera B, De La Barrera S, Gamache I, et al. Association of IGF-1 Levels With Height From Childhood to Adulthood: An Observational and Mendelian Randomization Study. J Clin Endocrinol Metab 2026;111:e651-8. [Crossref] [PubMed]
25. Zilberberg KS, Yackobovitch-Gavan M, Tenenbaum A, et al. Can Growth Hormone Stimulation Tests in Children Predict the Response to Growth Hormone Treatment? Endocr Pract. 2025;31:731-8. [Crossref] [PubMed]
26. Hu S, Zhang X, Li Y, et al. A Reporter Gene Assay for Measuring the Biological Activity of PEGylated Recombinant Human Growth Hormone. Molecules 2025;30:669. [Crossref] [PubMed]