Metabolic and bone effects of long-acting polyethylene glycol-recombinant human growth hormone in growth hormone deficiency during the transition period: a prospective study

Article information

Ann Pediatr Endocrinol Metab. 2026;31(3):178-188

Publication date (electronic) : 2026 June 30

doi : https://doi.org/10.6065/apem.2550238.119

Ke Huang^1,*, Hu Lin^1,*, Lifen Chen², Zhiya Dong², Yanhong Li³, Guimei Li⁴, Hui Yao⁵, Shouyue Sun^,2, Junfen Fu^,1

¹Children's Hospital Zhejiang University School of Medicine, Hangzhou, China

²Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China

³The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

⁴Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

⁵Wuhan Children's Hospital (Wuhan Maternal and Child Health Hospital, Wuhan Women's and Children's Health Care Center), Wuhan, China

Address for correspondence: Shouyue Sun Department of Endocrinology, Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China Email: ssy10926@rjh.com.cn

Address for co-correspondence: Junfen Fu Children's Hospital Zhejiang University School of Medicine, Hangzhou 310003, China Email: fjf68@zju.edu.cn

*These authors contributed equally to this study as co-first authors.

Received 2025 July 20; Revised 2025 December 4; Accepted 2026 January 6.

Abstract

Highlights

· Polyethylene glycol-recombinant human growth hormone (PEG-rhGH) persistently elevates insulin-like growth factor-1 SDS in transition Growth hormone deficiency patients over 64 weeks; PEG-rhGH increases lean mass while reducing fat percentage and triglycerides effectively; PEG-rhGH shows favorable safety without drug-related adverse events.

Introduction

Growth hormone deficiency (GHD) is an endocrine metabolic disorder characterized by insufficient secretion of growth hormone (GH) from the anterior pituitary gland, with short stature as the prominent clinical symptom [1]. Transitional GHD occurs during the transition period or continues from childhood-complete GHD [2]. The transitional period refers to the phase between cessation of linear growth in late adolescence, characterized by a growth rate of less than 1.5 to 2.0 cm per year, and attainment of full adult maturity. This phase typically spans 6 to 7 years. GHD during the transition period often leads to systemic changes, including decreased bone mass (bone mineral density, BMD), increased adiposity, decreased lean body mass (LBM), elevated cholesterol and triglycerides (TGs), risk of atherosclerosis, altered structural parameters of the heart, and disruption of the hypothalamic-pituitary-gonadal axis [3,4].

GH is a polypeptide hormone synthesized and secreted by the anterior pituitary gland of the human body. GH promotes protein synthesis, lipolysis, bone growth and development, and regulates various physiological functions including human metabolism during transitional periods. Additionally, it plays a crucial role in metabolic regulation. Therefore, children diagnosed with GHD typically require treatment with recombinant human GH (rhGH) to address growth disorders and metabolic abnormalities associated with GHD [5].

The primary objective of administering rhGH for treatment of GHD in pediatric patients is to promote growth. However, its significance extends beyond this, as it also plays an indispensable role in maintaining body composition and metabolic equilibrium during both the transitional and adult phases. Many studies have shown that GH treatment during the transition period has a positive impact on patients' bone mass in adulthood [6,7]. Moreover, transitional GH therapy has been shown to increase LBM, muscular strength, and muscle-to-fat ratio [8,9]. In a prospective study, adolescents with GHD exhibited a significant increase in low-density lipoprotein cholesterol (LDL-C) and TG levels, along with a decrease in left ventricular mass index and mitral inflow velocity ratio, 6 months after discontinuing GH therapy. These parameters showed improvement upon the resumption of treatment [10].

The majority of rhGH available for clinical use is short-acting GH that requires daily injections for many years, leading to pain and inflammation at the injection site, reducing the patient's quality of life, and impacting treatment adherence [11]. Low patient compliance can further compromise treatment efficacy [12]. Therefore, there is an urgent demand for long-acting GH therapies that are both safe and effective.

Jintrolong (GeneScience Pharmaceuticals, China), a polyethylene glycol rhGH (PEG-rhGH), is the first commercial long-acting rhGH preparation approved in China. The conjugated PEG can hydrate and increase the molecular volume of rhGH, thereby reducing the clearance rate through renal filtration and prolonging the half-life of rhGH, effectively mimicking the biological effects produced by physiological pulses of endogenous GH. The safety and efficacy of PEG-rhGH in the treatment of GHD in pediatric patients have been extensively validated [13,14]. Furthermore, numerous studies have also demonstrated that PEG-rhGH and short-acting rhGH have comparable effects [15], and patients using PEG-rhGH demonstrated superior treatment adherence [16].

Although a number of studies have been conducted to explore the efficacy and safety of long-acting GH, most have focused on pediatric or adult populations, with few addressing the important period of transition [17,18]. Consequently, this study aims to assess the efficacy and safety of PEG-rhGH in treating GHD during the transition period, thereby providing a clinical reference for the utilization of PEG-rhGH in managing GHD.

Materials and methods

1. Study design

This study was a prospective, multicenter and single-arm study (ChiCTR2100048579). It was conducted in accordance with the research protocol and approved by the Ethics Committee of The Children's Hospital, Zhejiang University School of Medicine (approval No. 2021-IEC-019), with written informed consent obtained from all participants' parents/legal guardians. Eligible participants were given diet and exercise-guided PEG-rhGH (Jintrolong) for a duration of 64 weeks. The overall study period was 66 weeks, comprising a trial screening phase of 2 weeks, a dose-adjustment period of 12 weeks, and a trial drug treatment phase of 52 weeks (Fig. 1). A total of 10 visits were conducted during the study.

Fig. 1.

Blood sampling for IGF-1 in the main study period and dose titration of weekly polyethylene glycol-recombinant human growth hormone. The starting dose was 1 mg/wk. The dose adjustment period was within 0–12 weeks of administration. The IGF-1 SD adjustment target was 0 SD. Once-weekly polyethylene glycol-recombinant human growth hormone (Jintrolong) for 0–12 weeks. Increment/ reduction at 5th/9th/13th week. Time axis is not to scale. IGF-1, insulin-like growth factor-1; SD, standard deviation.

Results

1. Demographic and baseline characteristics

Baseline characteristics of the participants are shown in Table 1. This study commenced on September 24, 2021, and end time for patient enrollment was June 30, 2023. The follow-up phase was completed in August 2024. A total of 31 subjects were included, including 23 males (74.2%) and 8 females (25.8%), with a mean age of 20.46 years, ranging from 14.8~25.8 years. All subjects reported stable disease, most had received alternative treatments, and the mean duration of disease was 7.79 years. Most of the subjects did not have a history of smoking and alcohol consumption, and a few had a family history of diabetes, hypertension and cardiovascular disease. Nine patients (29.0%) developed the disease after pituitary surgery, 13 patients (42.0%) had pituitary stalk interruption syndrome, and 9 (29.0%) had other etiologies, such as hypopituitarism of the anterior pituitary gland, idiopathic hypogonadotropic hypogonadism, or combined hypopituitarism.

Table 1.

Demographic and baseline characteristics (N=31)

3. IGF-1 levels

IGF-1 is commonly utilized as a biomarker for monitoring the response to GH therapy. Longitudinal analysis revealed significant improvements in IGF-1 parameters throughout the 64-week study period. The IGF-1 SDS scores demonstrated progressive elevation from baseline (-3.07) to 38 weeks (-1.24) (P<0.001), maintaining therapeutic efficacy at 64 weeks with -1.38 (P<0.001) (Supplementary Table 3; Fig. 2). Furthermore, subgroup analysis by sex indicated that the IGF-1 SDS significantly increased from baseline (-3.07) to 64 weeks (-1.21) (P<0.001) in male subjects, and, similarly, significantly increased from baseline (-3.05) to 64 weeks (-1.80; P=0.014) in female subjects (Supplementary Table 4). Subgroup analysis by etiology (Supplementary Table 5) exhibited some differences: for the subjects who developed GHD after pituitary surgery, the IGF-1 SDS significantly increased from baseline (-3.02) to 64 weeks (-1.35) (P=0.031 for both); for the subjects with continuation from childhood GHD, the IGF-1 SDS from baseline to 64 weeks was -2.66 to -0.87 (P=0.002); for the subjects with GHD caused by other etiologies, the IGF-1 SDS from baseline to 64 weeks was -3.15 to -1.90 (P=0.024). As such, the IGF-1 SDS in all subgroups was significantly elevated.

Fig. 2.

IGF-1 SDS. *Baseline vs. 38 weeks. **Baseline vs. 64 weeks. SD, standard deviation; IGF-1, insulin-like growth factor-1; SDS, SD score.

4. Body composition changes

Significant alterations in body composition parameters were observed throughout the study period. Body weight demonstrated a clinically meaningful elevation of 3.96 kg (P<0.001), while, paradoxically, whole-body adiposity exhibited a nonsignificant downward trend (-0.54 kg; P=0.413) (Table 2). The body weight SDS exhibited significant elevation from baseline (0.67) to 64 weeks (1.14) (P=0.005), and BMI SDS also showed significant elevation from baseline (0.74) to 64 weeks (1.03) (P=0.011). Of particular physiological significance was the robust 4.54 kg augmentation in LBM (P<0.001) (Table 2; Fig. 3B). Notably, there was a statistically significant reduction in whole-body Fat% from 37.40% to 33.94% (Δ2.70%, P=0.008) and Fat% SDS from 1.91 to 1.47 (P=0.009), demonstrating clinically meaningful improvements in body composition parameters (Table 2; Fig. 3A). Subgroup analysis by sex indicated some differences: in male subjects, body weight increased 4.10 kg (P=0.030), body weight SDS increased 0.42 (P=0.038), LBM increased 5.52 kg (P=0.003), and Fat% decreased 9.71% (P=0.004); in female subjects, body weight increased 3.62 kg (P=0.026), body weight SDS increased 0.48 (P=0.039), LBM increased 2.07 kg (P=0.060), and Fat% increased 0.14% (P=0.950), demonstrating that the effects of PEG-rhGH on the changes of LBM and Fat% may be different between male and female GHD patients. Subgroup analysis by etiology exhibited some differences: for the subjects who developed GHD after pituitary surgery, there was no significant change in body composition parameters; however, for the subjects with continuation from childhood GHD, body weight increased 4.44 kg (P=0.027), body weight SDS increased 0.50 (P=0.039), LBM increased 6.04 kg (P=0.004), and Fat% decreased 12.86% (P=0.027). For the subjects with GHD caused by other etiologies, there were significant changes in body weight, body weight SDS, and LBM, but no significant change in Fat%.

Table 2.

Body composition changes

Fig. 3.

Body composition changes. (A) Whole-body fat mass percentage (Fat%). (B) Lean body mass. *Baseline vs. 38 weeks. **Baseline vs. 64 weeks.

5. Bone density

While the lumbar BMD z-score change did not reach statistical significance (P>0.05), an absolute increase of 0.43 points was demonstrated, with values improving from -1.54 at baseline to -1.12 postintervention (Table 2; Fig. 4).

Fig. 4.

Lumbar BMD z -score. BMD, bone mineral density. *Baseline vs. 38 weeks. **Baseline vs. 64 weeks.

Discussion

This study aimed to evaluate the efficacy and safety of PEG-rhGH in the treatment of GHD during the transition period. The results showed that PEG-rhGH was effective in increasing IGF-1 levels and LBM and decreasing the percentage of body fat and TG levels. During the treatment period, there was a favorable trend in treatment adherence, accompanied by a low incidence of adverse events.

IGF-1 is significantly influenced by GH [21], exhibiting age-dependent variations in the human body. During the growth phase, blood levels of IGF-1 progressively rise from a basal state to a peak, subsequently declining with advancing age [22]. Consequently, the expression level of IGF-1 serves as a critical indicator of pediatric growth and can be utilized to assess the efficacy of rhGH in treating GHD [23]. In the present study, the elevation of IGF-1 SDS was significant, and the IGF-1 SDS increased from -3.19 to -1.59, attaining the normal range (-2.0 to +2.0 SD) [24]. In previous studies, the dosages ranged from 0.12 mg/kg/wk to 0.66 mg/kg/wk, and IGF-1 SDS=0 was often achieved after a period of dosing [25-28]. Another study reported that the changes in IGF-I SDS levels were significantly dose-dependent during GH replacement therapy for GHD [24].

It has been shown that in adolescents with severe GHD, interruption of rhGH therapy leads to an increase in cardiovascular risk, as indicated by elevated levels of TC, LDL-C, and apolipoprotein B, as well as decreased HDL-C [29,30]. Conversely, maintenance therapy during the transition period was able to reduce adiposity, increase LBM and bone density, and improve bone cortex and trabecular structure [24,31]. GH inhibits adipogenesis by inhibiting the formation of preadipocytes from stem cells or the recruitment of stem cells to the fat depot [32]. In our investigation, the primary endpoint of change in whole-body fat percentage showed a significant decrease after 64 weeks of treatment. Many studies reported that replacement of GH in adults with GHD reduces fat mass and increases lean mass [24,33]. It is speculated that the change of fat and lean mass may be correlated to increases in IGF-1 levels [34,35]. In addition to the direct calculation of fat mass and percentage, blood lipid levels also reflect the body's fat metabolism. TG are an important source of energy for cellular metabolism, but higher levels can lead to adverse cardiovascular events [36]. In this study, the reduction in TG levels was statistically significant. PEG-rhGH was effective in decreasing the percentage of body fat and TG, leading to LBM. This finding further corroborates that GH facilitates adipose tissue differentiation and lipolysis [37,38]. This has general implications for the prevention of obesity-related complications in patients with GHD during the transition period.

GHD may result in insulin resistance, consequently leading to the dysregulation of glucose and lipid metabolism. This condition also elevates the risk of cardiovascular disease, osteoporosis, and muscle mass depletion [39-41]. GH promotes increases in muscle mass and bone mass through a number of mechanisms [41]. The main components of LBM are muscle and bone, and LBM gain is important for increasing basal metabolic rate and improving physical function and health. Our findings showed a significant increase in LBM, which is similar to the results of previous studies [42]. Interestingly, sex differences in the response to PEG-rhGH were observed in our study. Changes in IGF-1 levels, LBM, and body fat were more pronounced in men, indicating that men with GHD appear more responsive to PEG-rhGH therapy than women with respect to the increase in IGF-1 levels and improvement in body composition, which was also observed in a previous study [43]. Subgroup analysis by etiology showed that the changes in IGF-1 levels and body composition in childhood-onset GHD patients were more sensitive to the PEG-rhGH therapy compared with the other subgroups.

No statistically significant alterations in bone density were detected. Previous research has demonstrated that bone resorption predominates during short-term therapy (6–12 months), with rhGH initially triggering an intense bone resorption process that overshadows bone tissue formation. After 12 months, bone formation typically becomes predominant, leading to increased bone mass in patients [42]. Nonetheless, considering the bone-promoting effects of IGF-1, an increase in bone mass would be observed. A previous study in young GHD adults demonstrated a significant dose response to GH replacement therapy in the increase in spine BMD at 24 months [24]. In this study, the lumbar BMD z-score demonstrated an absolute improvement of 0.43 points at 64 weeks of observation, although statistical significance was lacking. Therefore, we posit that the lack of significant change in bone mass in this study may be attributed to an insufficient follow-up duration and a lower dose of rhGH, which are areas for potential improvement. Overall, GH treatment improved body composition, especially in male subjects.

Nonetheless, because most rhGH preparations currently used for GHD are short-acting, frequent injections result in localized pain, which not only impacts patient comfort but also contributes to decreased adherence. PEG-rhGH requires only a weekly injection, offering the advantages of convenient administration and improved pediatric compliance. Patient adherence in this study was as high as 97.69% (0.0599 [Is this standard deviation?]). The results of a meta-analysis showed that in pediatric patients, patient adherence to treatment with rhGH ranged from 7% to 71% [44]. It has also been confirmed that patient adherence to weekly administration is substantially higher compared to daily administration [45]. These studies offer additional substantiation that long-acting rhGH administered once a week significantly improves treatment adherence compared to short-acting rhGH injected daily, which is important for improving patient outcomes and achieving therapeutic goals.

For adolescents with GHD in the transition period—especially those with high-risk comorbidities such as diabetes—the interval between dose adjustments should be extended and glucose monitoring intensified. GH dosing should be individualized and titrated against serum IGF-1 concentrations. Treatment should begin with a low dose (0.1–0.2 mg/day) and be gradually uptitrated to achieve age-adjusted IGF-1 levels within the reference range (IGF-1 SDS between -2 and +2), with the primary goal of minimizing adverse effects [46].

This study was a prospective, multicenter study that featured detailed data collection, minimized recall bias, and yielded generalizable results. However, it is important to acknowledge that the study was not without limitations. The small number of subjects included in this study may have affected the validity of the findings to some extent. In addition, the present study was conducted over a period of 64 weeks, which is not long enough for follow-up of bone changes. The dose of PEG-rhGH used in this study was low, and therefore the improvement of some indicators was not significant. PEG-rhGH dosing was individualized and titrated against serum IGF-1 concentrations. At each follow-up visit, the regimen was adjusted on the basis of the patient’s 2-hour oral glucose tolerance test, fasting glucose, and HbA1c values. Treatment started at 1 mg/wk and was gradually up-titrated until age-adjusted IGF-1 levels were within the reference range (IGF-1 SDS -2 to +2), unlike in childhood-onset GHD, where the initial dose is typically 0.2 mg/kg/wk and subsequently individualized according to growth response, serum IGF-1 levels, and individual tolerability. However, this study could provide guidance on the dosage of drugs used for clinical treatment. Future research should aim to expand on these findings with larger, longer-term studies that include a control group.

In conclusion, PEG-rhGH, as a long-acting GH, significantly improves IGF-1 levels and alters body composition parameters by increasing the LBM and decreasing the percentage of body fat and TG levels in patients with GHD during the transition period. This study also demonstrates that PEG-rhGH has a comparable safety profile and helps improve therapeutic adherence. In summary, the evidence from this study suggests that PEG-rhGH is effective and well-tolerated, therefore having therapeutic potential in patients with transitional GHD.

Supplementary materials

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