Retrospective analysis of growth hormone effects on growth and adenoma volume in children with pituitary microadenoma

Introduction

As a common intracranial tumor, pituitary microadenoma (PM) is mostly benign, but its occurrence in children brings many challenges to the growth and health of children (1). Childhood is a key stage for the rapid growth of the body and the gradual maturity and perfection of the endocrine system (2,3). As the core hub of the endocrine system, the pituitary gland, once microadenoma lesions occur, a series of problems such as hormone secretion imbalance and growth and development obstruction may follow (4). Although the incidence of PM in children is lower than that in adults, it is increasing year by year. According to foreign multi-center epidemiological studies, the prevalence of PM was 5 per 1,000, which represented 12.9% of incidental lesions (5). Notably, pituitary adenomas account for only 1% of all childhood (<15 years) intracranial neoplasms, yet their incidence rises markedly with age. They increase from ~1% of intracranial tumours before age 15% to 18% in those aged 15–24 years, and represent 78% of pituitary-fossa lesions in children and young people. In the UK, cases diagnosed between 1997 and 2016 rose from 5 in 0–4 years old to 282 in 15–19 years old, reflecting a clear age-related upward trend (6).

This disease tends to occur in pre-adolescent children, when the growth spurt begins, and pituitary function is crucial for systemic development. Not all pituitary adenomas result in pituitary dysfunction; when present, this is typically partial and often correlates with tumor size (particularly in large adenomas) or treatment-related factors. Conversely, clinically non-secreting microadenomas generally do not cause new-onset pituitary hormone deficiencies, and complete hypopituitarism is uncommon (6-8). This is a result of interference with normal hormone secretion, either from direct compression of the pituitary gland or (in the case of hyperprolactinemia) inhibition of the pulsatile secretion of luteinizing hormone (LH), leading to inadequate gonadal stimulation (7). In hypogonadotropic hypogonadism, which is caused by disorders of the hypothalamus or pituitary, gonadotropin-releasing hormone (GnRH) and gonadotropins (such as follicle-stimulating hormone and LH) are either deficient or inactive, leading to decreased secretion of gonadal sex steroids, presenting with normal or arrested pubertal development and amenorrhea in adolescent girls (9). PM often causes dysregulated secretion of growth hormone (GH) (7,10); excessive secretion may lead to gigantism, while insufficient secretion can result in growth retardation or short stature (4,11).

At present, the incidence of children with stable PMs and compromised predicted adult height (PAH) is a topic that has drawn increasing attention in recent years. The study has indicated that this incidence may be higher than previously thought, highlighting the importance of early detection and appropriate treatment strategies (12). GH plays a crucial role in the growth and development of children. A large number of studies have provided solid evidence for the effectiveness and safety of GH in treating short children. Meta-analyses and large-scale clinical trials have shown that GH therapy can significantly improve the height of children with short stature. It promotes bone growth, enhances protein synthesis, and improves overall growth parameters (13-15). However, when it comes to children with PM and short stature, the use of GH is controversial. There is a concern that GH may stimulate the progression of PM, potentially leading to the delay or even abandonment of GH therapy. Ultimately, this could result in frustration for these children and their families due to losing the chance to pursue a normal adult height (16). The growth-promoting effect of GH is achieved through a series of complex physiological mechanisms (17). Moreover, GH binds to GH receptors (GHR) on the surface of target cells, activating multiple signaling pathways such as Janus kinase/signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein kinase (MAPK), which may potentially interact with the abnormal cell growth mechanisms in PM (18,19).

In pediatric practice, recombinant human growth hormone (rhGH) is used for growth failure due to GH deficiency and selected non-GHD conditions. In this cohort, rhGH was initiated to preserve height potential in children with stable PMs who had compromised PAH, despite not necessarily meeting the anthropometric definition of short stature in childhood. Leuprolide (a GnRH analog) is the standard therapy for central precocious puberty (CPP) or rapidly progressive puberty characterized by advanced and accelerated BA. We retrospectively reviewed 22 children treated with rhGH + leuprolide, systematically tracking growth metrics, hormone profiles, and interval imaging. GH did not promote microadenoma growth and was well tolerated in this series, supporting cautious, individualized use in children with PM and height impairment (compromised PAH). We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-679/rc).

Methods

Clinical information

A single-centre retrospective cohort study was conducted at The Affiliated Hospital of Guizhou Medical University, including 29 children with stable PMs and compromised PAH who received rhGH between 2016 and 2024; data were abstracted from medical records. A preliminary screening was conducted on 29 children with PM, and seven patients were excluded. Among them, five cases were unable to obtain complete information due to changes in the hospital’s electronic system, one case was unable to provide examination of magnetic resonance imaging (MRI) images from other hospitals before treatment for reading the film again, and the other case refused to undergo reexamination after treatment due to busy academic schedules. The seven excluded cases after GH treatment showed no clinical discomfort, and six of them underwent dynamic contrast-enhanced MRI of the sellar region after treatment without enlargement of the pituitary mass. Therefore, the final analysis included 22 children. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Affiliated Hospital of Guizhou Medical University Ethics Committee (ethics approval No. 2025138K). For this retrospective study, the Ethics Committee waived the requirement for written informed consent because the study involved minimal risk to participants and used de-identified data.

Inclusion and exclusion criteria

Inclusion criteria

To be eligible for participation, all subjects had to meet the following criteria: (I) to be eligible, participants had to have compromised PAH, defined as PAH <−2.0 standard deviation score (SDS) or below the lower bound of target height. (II) Skull MRI confirmed PM with a tumor diameter less than 10 mm and clear imaging features showing that the tumor was located in the pituitary gland. Baseline endocrine evaluation (GH-IGF-1, thyroid, gonadal, adrenal, and prolactin axes) showed no biochemical hypersecretion, and patients with functioning adenomas or other defined endocrine disorders were excluded; thus, all included lesions were clinically non-functioning at baseline. (III) A follow-up pituitary MRI performed at least 3 months apart prior to GH therapy showed no increase in the size of the microadenoma, suggesting a non-progressive PM. (IV) No space-occupying lesions other than a PM were present. (V) The age range was set for children and adolescents between 8 and 18 years old. (VI) Nutritional status, thyroid function, and adrenal cortical function were normal prior to initiation of GH therapy.

Exclusion criteria

In this retrospective study, subjects were excluded if they had other severe intracranial lesions, severe heart/liver/kidney dysfunction, including New York Heart Association heart function grade III and above, Child-Pugh liver function grade B and above, chronic kidney disease stage (4–5), a history of mental illness, allergic reactions to study drugs or their excipients, or had received other specific PM treatments within 3 months before enrollment.

Treatment

The pre-treatment endocrine evaluation documented that the thyroid axis and adrenal cortex axis in the hypothalamic pituitary target axis of the patient were normal. Pubertal status was assessed clinically using Tanner staging of breast/genital (B/G) and pubic hair (P) development and recorded at the time of GH initiation. Serum IGF-1 was interpreted with BA- and sex-specific reference ranges. When growth hormone deficiency (GHD) was suspected, GH stimulation testing (levodopa + pyridostigmine; institutional diagnostic cut-off 10 ng/mL) was performed according to routine clinical practice; children who met GHD criteria received GH as replacement therapy. In children with compromised PAH, with rhGH (Jintropin; GeneScience Pharmaceuticals, Changchun, China) was prescribed to improve PAH. Treatment was delivered within routine care after specialist counselling. Leuprolide was used according to standard criteria for rapidly progressive puberty or CPP with advanced BA.

All patients received rhGH as a subcutaneous injection nightly, and leuprorelin was additionally administered in those who met the criteria for CPP or rapidly progressive puberty. (I) All patients received rhGH as a subcutaneous injection nightly before bedtime. Initial rhGH doses were individualized according to international and Chinese pediatric GH guidelines and to the underlying diagnosis. In children with GHD, the starting dose was determined by GH stimulation test results and pubertal status: those with complete GHD (peak GH <5 ng/mL) received 0.1 IU/kg/day, those with partial GHD (peak GH ≥5 ng/mL) received 0.15 IU/kg/day if prepubertal and 0.2 IU/kg/day if already in puberty. In children with a normal GH axis but compromised PAH—namely CPP (n=3), idiopathic short stature (n=2), and rapidly progressive puberty (n=12)—rhGH was initiated at 0.2 IU/kg/day (approximately 0.067 mg/kg/day). During treatment, rhGH doses were titrated according to serum IGF-1 levels. When IGF-1 persistently exceeded +2 to +3 SDS for bone age and sex, the rhGH dose was reduced and IGF-1 was rechecked after approximately 1 month; if IGF-1 remained elevated, rhGH was temporarily discontinued and potential underlying causes were actively investigated. (II) Leuprorelin may be prescribed—alone or in combination with rhGH—for CPP or rapidly progressive puberty with advanced BA and compromised PAH, dosing followed standard regimens. The initial dose of leuprorelin acetate was 3.75 mg subcutaneous injection every 4 weeks. Subsequent doses (approximately 100–120 µg/kg per injection) were adjusted according to pubertal suppression and weight gain, with a maximum dose of 3.75 mg every 4 weeks. CPP was defined by age-inappropriate secondary sexual characteristics with advanced BA and evidence of hypothalamic-pituitary-gonadal (HPG)-axis activation; rapidly progressive puberty denoted accelerated pubertal progression with advanced BA and declining PAH relative to target height.

Data collection time setting

Data were abstracted from routine-care records using pre-specified analysis windows to describe treatment trajectories. At baseline (pre-initiation), we recorded each child’s demographic data; growth and development parameters, including height, BA, height standard deviation score (HtSDS), and PAH; fasting blood glucose (FBG), fasting insulin (FINS), insulin-like growth factor-1 (IGF-1), thyroid-stimulating hormone (TSH), free serum triiodothyronine (FT3), and free serum thyroxine (FT4). PAH-SDS was derived using the World Health Organization (WHO) 2007 height-for-age (5–19 years) sex-specific lambda-mu-sigma (LMS) parameters at 19 years (228 months). The LMS z-score was computed as z = [(x/M)^L − 1]/(L·S), where x is PAH (cm), M is the sex- and age-specific median from the reference, L is the Box-Cox power, and S is the generalized coefficient of variation. During the treatment phase, identical assessments—including clinical measures and laboratory tests—were repeated every three months. Pituitary MRI was performed on a 3.0 T Siemens MAGNETOM Skyra using a 32-channel head/neck coil. For volumetry, sellar lesions were segmented in ITK-SNAP v3.8.0. IGF-1 SDS was calculated using BA- and sex-specific normative data supplied by the accredited laboratory, whereas other biochemical variables were interpreted against age-appropriate laboratory reference intervals without z-score conversion. MRI scan performed 3 months before initiating GH therapy demonstrated no increase in the size of the PM. Following at least 3 months of GH treatment, a follow-up MRI was obtained to assess changes in the microadenoma volume. A final evaluation was carried out at the end of therapy (last visit), ensuring a comprehensive, longitudinal portrayal of changes throughout the study period.

Laboratory assays

Fasting peripheral venous blood samples were obtained in the early morning after an overnight fast. Serum was separated within 2 hours and analyzed in the same certified hospital laboratory according to institutional protocols. FBG and FINS were measured using routine automated biochemical methods. Serum IGF-1 concentrations were quantified by standard chemiluminescent immunoassays, and results were interpreted using BA- and sex-specific reference ranges; IGF-1 values were expressed as IGF-1 SDS where appropriate. Thyroid function indices, including TSH, FT3, and FT4, were also measured by chemiluminescent immunoassays in the same laboratory. All assays were performed in accordance with the manufacturers’ instructions, and results were interpreted against age-appropriate laboratory reference intervals.

Detection indexes

In this study, standardized procedures were used for all auxological and radiological assessments. For growth and development, standing height was measured with a professional stadiometer as the vertical distance from the vertex to the heel in children standing barefoot and upright, in order to reflect longitudinal bone growth. BA was assessed from standardized X-ray images of the left hand and wrist. BA was determined according to the Greulich-Pyle (G-P) atlas by an experienced pediatric endocrinologist following institutional protocols, to characterize the dynamic changes in skeletal development and maturation. PAH was then estimated using the G-P method based on BA in combination with the observed trends in height gain and BA progression.

Regarding hormone- related indicators, peripheral venous blood samples were collected from the children. Serum samples of IGF-1 were quantitatively analyzed by chemiluminescence method to assess the realization degree of rhGH’s growth-promoting function and the activation status of the organism’s growth potential. High-resolution MRI with specialized scanning of the pituitary area was used to assess PM-related indicators. During scanning, parameters such as layer thickness, layer spacing, scan sequence, and imaging field were carefully adjusted according to MRI protocols specific to PM to ensure high-quality, high-contrast images. Professional image analysis software equipped with precise volumetric measurement capabilities was employed. Imaging diagnostic experts manually or semi-automatically delineated the tumor boundaries to calculate the PM volume accurately. This enabled dynamic monitoring of tumor atrophy or progression before and after treatment, thereby serving as a key indicator for evaluating the impact of GH therapy on tumors.

Statistical analysis

SPSS 25.0 statistical software was employed for data analysis. Continuous variables were expressed as descriptive statistics [mean ± standard deviation (SD)]. Comparisons of quantitative indicators within the same group before and after treatment (e.g., height, BA, BA-CA, HtSDS, and PAH) were performed using paired t-tests or paired nonparametric tests (Wilcoxon signed-rank test). Data from multiple time points with repeated measurements (e.g., safety indicators such as FBG, FINS, IGF-1, and IGF-1 SDS) were analyzed using repeated measures analysis of variance (ANOVA). Comparisons of PM volume at different time points (pre-treatment, during treatment, post-treatment) were performed using repeated measures ANOVA. All tests were two-tailed, and P<0.05 was considered statistically significant.

Results

Demographic analysis

In this study, a total of 22 patients were included, with 13 girls and 9 boys. At baseline, diagnostic categories were: GHD in 5 children, CPP in 3, idiopathic short stature in 2, and rapidly progressive puberty in 12, showing that precocious and rapidly progressive pubertal phenotypes were frequent in this cohort. Baseline Tanner staging was available for all 22 children: 19 were pubertal (Tanner stage ≥2 in B/G and/or P), whereas three remained prepubertal (Tanner stage 1) at the start of GH therapy. Medical consultation flowchart was shown in Figure 1. Baseline characteristics of the overall population and different subgroups are presented in Table 1. There were statistically significant age differences, the age at which leuprorelin treatment started, the age at which rhGH treatment started, PAH, and the difference between baseline BA and actual age among different sex subgroups (P value <0.05). At baseline, PAH-SDS (WHO 2007) indicated substantial population-referenced height impairment: overall −2.15±0.58, median −2.09 [interquartile range (IQR), −2.30, −1.82]. By sex, girls −1.97±0.55 vs. boys −2.35±0.60; the difference was not significant (P=0.28). These values align with the eligibility definition of compromised PAH.

Figure 1 Medical consultation flowchart. BA, bone age; CA, chronological age; CKD, chronic kidney disease; CPP, central precocious puberty; FBG, fasting blood glucose; FINS, fasting insulin; FT3, free serum triiodothyronine; FT4, free serum thyroxine; GH, growth hormone; HPG, hypothalamic-pituitary-gonadal; HtSDS, height standard deviation score; IGF-1, insulin-like growth factor-1; MRI, magnetic resonance imaging; NYHA, New York Heart Association; PAH, predicted adult height; PM, pituitary microadenoma; rhGH, recombinant human growth hormone; SD, standard deviation; TSH, thyroid-stimulating hormone.

Treatment efficacy

The mean duration of treatment with rhGH was 1.75 years, and the mean duration of treatment with leprerelin was 1.57 years. As shown in Figure 2 and Table 2, the difference between BA and CA decreased from 1.08 to 0.40 years following treatment, with a mean reduction of 0.68 years from baseline. Moreover, consistent with baseline impairment, a large proportion of children had PAH-SDS <−2.0 at entry (overall 53.3%, girls 50.0%, boys 57.1%), supporting the clinical relevance of PAH-targeted intervention. After rhGH therapy, the HtSDS improved by 0.41, and the PAH increased by 7.43 cm, both showing statistically significant differences (P<0.05).

Figure 2 Changes in key growth indicators before and after treatment. (A) The difference between BA and CA decreased significantly after treatment in both male and female patients. (B) HtSDS improved after GH therapy in both male and female patients. (C) PAH increased after treatment in both male and female patients. Statistical analysis was performed using student t-test. Data are presented as mean ± SD. Significant differences between before and after treatment are marked with: *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. BA, bone age; CA, chronological age; GH, growth hormone; HtSDS, height standard deviation score; PAH, predicted adult height; SD, standard deviation.

Security analysis

During the one-year treatment period, FBG and FINS levels remained generally stable, with a few cases exhibiting transient elevations that resolved with continued monitoring. IGF-1 and IGF-1 SDS also showed no significant long-term trends, although temporary elevations in IGF-1 were observed in some patients. These elevations subsided rapidly after dose reduction or temporary discontinuation of rhGH therapy and were not associated with any clinical symptoms. However, due to a high proportion of missing follow-up data, the effect sizes and P values for these indicators could not be reliably calculated (see Table 3 and Figure 3).

Figure 3 Trends in metabolic and growth-related indicators during the 1-year treatment period. (A) FBG levels remained generally stable. (B) FINS levels showed minor fluctuations but no sustained change. (C) IGF-1 levels exhibited transient elevations in some cases, which normalized after dose adjustment or temporary cessation of GH therapy. (D) IGF-1 SDS also showed no significant long-term trends. Statistical analysis was performed using student t-test. Data are presented as mean ± SD. Significant differences between before and after treatment are marked with: *, P<0.05; **, P<0.01. BA, bone age; FBG, fasting blood glucose; FINS, fasting insulin; GH, growth hormone; IGF-1, insulin-like growth factor-1; SD, standard deviation; SDS, standard deviation score.

Changes in MRI volume

To evaluate changes in the mean volume of PMs before and after treatment with rhGH, MRI scans were conducted at three time points: during the initial comprehensive evaluation for the cause of growth arrest, three months after the initial MRI scans (prior to initiating rhGH treatment), and at least 3 months following the commencement of rhGH treatment. No significant change in mean PM volume was observed between the pre-treatment and post-treatment periods. There was no evidence suggesting that rhGH therapy for short stature led to an increase in non-progressive pituitary microtumor volume (Table 4 and Figure 4). Although T1 > T2 (38.7 → 31.9 mm³), this decrease is more likely to be due to natural fluctuations rather than true biological changes. Moreover, after at least 3 months of rhGH treatment, the PM volume (T3) decreased by an average of 2.72 mm³ compared to the pre-treatment baseline (T2), with a P value of 0.18. This difference was not statistically significant, indicating no clear evidence that rhGH treatment contributes to an increase in PM volume (Table 5).

Figure 4 Mean volume of pituitary microadenomas at three time points. The mean volume of pituitary microadenomas showed no significant change across the three time points. MRI, magnetic resonance imaging.

Changes in thyroid function

To monitor potential endocrine disturbances during treatment, thyroid function indicators including TSH, FT3, and FT4 were regularly measured throughout the treatment period. As shown in Figure 5, no significant fluctuations or abnormal trends were observed in these parameters during or after the administration of rhGH and leuprorelin. These findings suggest that the combined therapy did not adversely affect thyroid function, further supporting the safety of this treatment regimen.

Figure 5 Thyroid function indicators during the course of treatment. (A) TSH, (B) FT3, and (C) FT4 levels remained stable throughout the treatment period. FT3, free serum triiodothyronine; FT4, free serum thyroxine; TSH, thyroid-stimulating hormone.

Discussion

PM is a distinct endocrine disorder in children and has drawn increasing attention due to its notable incidence among those with short stature (20). Current studies suggest that approximately 5% to 10% of children presenting with short stature may have an underlying PM (20).

GH plays a crucial role in promoting the growth of children. However, due to concerns that its use might trigger the progression of PM, both patients and doctors are extremely cautious when considering its prescription. Based on the risk that GH may cause secondary neoplasia (21), doctors may delay or avoid rhGH treatment for children suspected of having PM. Among the parents of children with short stature and suspected PM, the parents may express concerns about the potential risks associated with rhGH treatment, or misdiagnosis may cause the children to miss the best treatment period (22). This significantly impacts their potential for achieving normal height. This study aims to address this critical issue. By conducting a comprehensive and in-depth exploration of the treatment regimen involving rhGH, with leuprorelin added as clinically indicated, we employed a rigorous research design and meticulous data monitoring. Through this approach, we obtained a series of key findings. These results are of far-reaching significance as they not only contribute to a more profound understanding of this treatment strategy but also lay a solid foundation for future clinical practice and further scientific research expansion in the field of pediatric endocrinology. They offer valuable insights that can potentially guide more accurate treatment decisions and improve the overall prognosis for children with PM and short stature.

The results of this study showed that the height dimension improved significantly after treatment. After treatment, the height of the children increased from 144.4±9.4 to 156.6±9.6 cm, with an increase of 12.2±9.6 cm. The height standard deviation score (HtSDS_BA) increased from −0.52±0.80 to −0.12±0.83 (P=0.003), indicating that the combination therapy was effective in promoting growth. This is closely related to the core mechanism of action of rhGH. Exogenous rhGH supplement activates downstream signaling pathways such as JAK-STAT and MAPK, stimulating the liver to synthesize a large amount of IGF-1, which acts as a “growth driver” (23). It promotes the proliferation, hypertrophy, and matrix synthesis of bone growth plate chondrocytes in an all-round way, and restarts the growth process inhibited by PM (24). Leuprorelin acts on pituitary gonadotropin cells over an extended period (10). It desensitizes and internalizes the gonadotropin-releasing hormone receptor, thereby inhibiting the overactivity of the gonadotropin axis (10). This mechanism delays the progression of BA, preventing the premature closure of the epiphysis. As a result, it creates and prolongs a valuable time window for height growth, which aligns with the findings of previous research. In this study, leuprorelin was commonly used. Leuprorelin not only regulated the gonadotropin axis but also showed a positive impact on the overall treatment outcome for children with PM and short stature. It helped to coordinate with rhGH treatment, reducing the potential negative effects of early puberty-related bone development acceleration on final height. Additionally, during the treatment process, the use of leuprorelin was well-tolerated by most children. This further validates the rationality and effectiveness of its use in this combined treatment regimen. For example, a small-cohort study in Europe focused on children with prepubertal PM, which significantly accelerated height growth and delayed BA maturation after combined treatment, providing strong circumstantial evidence for the results of this study (25).

The results of this study showed that the regulation of BA after treatment was in line with expectations. BA increased from 12.5±1.9 to 13.6±1.4 years, an increase of 1.1±1.4 years, and the BA increased more slowly than actual age, which was in line with the normal growth and development rhythm control needs. Moderate BA promotion ensures the orderly maturation of bones, and the intervention of leuprorelin on the gonadal axis inhibits the BA advancement caused by premature and excessive sex hormone secretion, maintains the reasonable release of growth potential, and strengthens the foundation of benign regulation of the growth cycle by combined treatment. However, in this study, different age subgroups were not analyzed in this regard as the data mainly focused on gender subgroups. Future research with larger samples and appropriate age stratification is needed to explore whether there is age-related differences in BA regulation.

After treatment, the pituitary microtumor volume not only did not increase but also demonstrated a slight reduction. The mean volume changed from 31.97±25.93 to 29.25±27.32 mm³, and the P value of 0.1865 indicated no significant difference. During the treatment with rhGH in this study, a remarkable finding was that no progression of PM was observed in the participating children. This outcome is of great significance as it alleviates the concerns of both medical professionals and patients’ families regarding the potential risk of tumor progression associated with rhGH use. rhGH is mainly used to address growth retardation in children with PM. Although there were initial concerns that it might stimulate the growth of PM, the results of this study showed otherwise. The complex physiological regulation mechanisms in the body may play a role. rhGH may not have a promoting effect on PM as previously feared (12,26). Instead, it may have a balanced interaction with the body’s internal environment. In addition, the co-administration of leuprorelin, which is used to regulate the gonadotropin axis and delay BA progression, did not seem to have any adverse impact on the PM either. The combined use of these two drugs did not lead to tumor progression, suggesting that this treatment regimen is relatively safe in terms of non-progressive benign tumor development (12). This provides valuable evidence for the clinical application of rhGH in children with PM and short stature, and offers a reference for future treatment decisions.

In the exploration of differences in gender subgroups in this study, age-subgroup analysis was not the main focus. However, in future research, it is necessary to comprehensively consider different age-subgroup analyses. For example, analyzing the differences in treatment effects between different age-subgroup patients can help in more precise treatment. If considering age-subgroup analysis, it may be found that the growth and development regulation effect of combined treatment has different manifestations in different age groups. Younger patients may have different responses to treatment due to differences in physiological development, such as a longer time may be needed to develop growth potential, and the response and utilization of rhGH may vary with age (12,27).

In safety considerations and responses, notably, although some patients experienced transient and mild increase in FBG during the treatment, it did not significantly affect the overall mean values of blood glucose-related indicators. Moreover, in some cases, higher IGF-1 SDS levels were observed. However, through close monitoring, dose reduction, or drug discontinuation, these indicators returned to normal levels. These findings suggest that, with proper monitoring and timely interventions, the combined therapy demonstrates a favorable safety profile with respect to IGF-1-related responses. It further supports the idea that this treatment regimen can be managed effectively in a clinical setting, and the potential risks associated with IGF-1 fluctuations can be well-controlled, thereby ensuring the overall safety of the treatment for children with PM and short stature. In addition to glucose metabolism and IGF-1 regulation, thyroid function was also carefully monitored to assess broader endocrine safety. The levels of TSH, FT3, and FT4 remained within normal ranges throughout the treatment period, with no significant fluctuations or abnormal trends observed. These results indicate that the administration of recombinant human GH combined with leuprorelin did not negatively affect thyroid function. The maintenance of stable thyroid hormone levels further reinforces the endocrine safety of this combined regimen, suggesting that it does not pose additional risks to the hypothalamic-pituitary-thyroid axis in pediatric patients.

Research limitations

Our cohort included only children with PMs that were radiographically stable for ≥3 months before GH therapy, and whose pre-treatment endocrine evaluation documented normal hypothalamic–pituitary–thyroid and hypothalamic–pituitary–adrenal axes at baseline. This design inherently selects a healthier, lower-risk group and may skew safety and efficacy estimates in a favorable direction. Therefore, the findings should not be generalized to all pediatric microadenomas—especially those with progressive lesions or axis dysfunction—and should be interpreted cautiously. Prospective studies that include higher-risk phenotypes are needed to test generalizability. Due to the small sample size of only 22 patients, the breadth and depth of the conclusions are limited. Future studies should adopt international multi-center approaches with larger sample sizes across diverse geographical regions and ethnic groups to better detect rare and subtle therapeutic effects as well as potential adverse reactions. Additionally, many uncertainties remain regarding the long-term impacts on adult height, endocrine health, and tumor recurrence in children. Therefore, it is imperative to establish structured, long-term follow-up mechanisms incorporating digital health tools, remote patient monitoring, and systematic periodic evaluations. Moreover, current mechanisms are mostly macro; single-cell sequencing, proteomics, and organoids can illuminate cellular/molecular drivers of pituitary cell fate with combined therapy. These methods can facilitate the identification of sensitive biomarkers for precise patient stratification, guiding personalized therapeutic strategies and moving us closer to realizing a curative paradigm for pediatric PMs.

Conclusions

In conclusion, rhGH therapy demonstrates notable efficacy in promoting growth and development in children with short stature and appears to be safe for use in patients with non-progressive PM. The overall treatment regimen shows promising effectiveness and acceptable preliminary safety, offering valuable reference for clinical decision-making and individualized management strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-679/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-679/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-679/prf

Funding: The research was supported by The Beijing Medical Award Foundation (No. YXJL-2025-0296-0022).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-679/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Affiliated Hospital of Guizhou Medical University Ethics Committee (ethics approval No. 2025138K). For this retrospective study, the Ethics Committee waived the requirement for written informed consent because the study involved minimal risk to participants and used de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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