Growth hormones (GH) play a crucial role in promoting linear growth. It is widely used to treat growth disorders, including growth hormone deficiency (GHD), short stature in children born small for gestational age (SGA), and other syndromic conditions (1). Beyond its essential role in linear growth, GH treatment also influences metabolic regulation by normalizing lean body mass, supporting glucose metabolism and insulin secretion (2), and improving cardiovascular lipid profiles, and potentially reducing metabolic risk factors (3).

GH serves as a lipolytic hormone that promotes energy expenditure and reduces visceral fat (4). In adults with GHD, GH treatment can improve lipid profiles by lowering total cholesterol and low-density lipoprotein (LDL) cholesterol levels (5, 6). Additionally, GH treatment has been associated with reductions in body mass index (BMI) and visceral adiposity (7). Untreated adults with GHD have an increased risk of complications, including cardiovascular and liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD), and insulin resistance (8). In pediatric patients with GHD, the metabolic effects of GH remain poorly documented, as most existing studies have primarily focused on its role in promoting linear growth. However, some retrospective studies have reported significant improvements in various components of metabolic syndrome among children and adolescents with GHD (9, 10). Furthermore, when GHD results from underlying conditions such as craniopharyngioma requiring surgical intervention, the metabolic benefits of GH treatment remain controversial (11, 12).

For children with SGA, GH treatment facilitates catch-up growth and improves the final adult height. However, patients with SGA have an elevated risk of various metabolic complications during catch-up growth. In adulthood, they may also experience increased insulin resistance, obesity, and cardiovascular diseases (13). Studies suggest that GH treatment is most effective in improving final adult height when started early, maintained for a longer duration, and administered at higher doses (14). However, given the necessity of minimizing side effects, the management of GH treatment in this population presents a unique challenge. Close monitoring of lipid and glucose metabolism indicators throughout GH treatment is strongly recommended to ensure both safety and effectiveness. Nevertheless, there is an ongoing debate regarding the potential metabolic risks and benefits associated with GH treatment. Some studies indicate that GH treatment may increase glucose and insulin levels (4), whereas others highlight its positive effects on lipid metabolism (15).

To address this knowledge gap, we aimed to clarify the effect of GH treatment on the growth and metabolic parameters of pediatric patients with GHD and SGA by analyzing data from a large observational cohort, thereby providing valuable insights into its overall benefits and risks.

This study demonstrates that long-term GH treatment in patients with GHD and SGA is effective in improving metabolic parameters, particularly BMI, hepatic indices, and lipid profiles, over a 5-year follow-up period and also promotes linear growth. Our findings align with those of previous studies (19, 20), indicating that GH treatment leads to a substantial increase in height SDS in both groups, with a more pronounced response over time in patients experiencing hormone deficiencies or restricted fetal development. The greatest height SDS increase occurred in the first year of treatment, reaching 0.78 ± 0.38 (GHD: 0.78 ± 0.37; SGA: 0.79 ± 0.31; GHD and SGA: 0.80 ± 0.44), which is consistent with the results of previous studies reporting a first-year increment of 0.72 SDS. After 5 years of treatment, the total height SDS gain was 1.78 ± 0.94, 1.94 ± 0.82, and 1.64 ± 0.85 in the GHD, SGA, and GHD and SGA groups, aligning with the findings of other long-term observational cohort studies. For example, the Kabi/Pfizer International Growth Database (KIGS) cohort study (21, 22) reported median near-adult height (NAH)-SDS gains of 1.79 in boys and 2.07 in girls with idiopathic GHD. In the SGA group, the reported gains were 1.34 and 1.57 in boys and girls, respectively. However, in this study, the greater height gain observed in the SGA group after 5 years may be partly explained by the smaller number of patients who completed the full 5-year follow-up in this subgroup.

Additionally, the weight SDS exhibited significant improvements at all time points, although the BMI trends varied over different periods. The initial decline in BMI SDS during the first year of treatment may be attributed to the rapid increase in height, resulting in a relative reduction in BMI. However, BMI gradually increased over time, approaching the average range as treatment continued. Similar trends have been reported in other studies (15, 21), where BMI did not consistently increase in either the GHD or SGA groups. Notably, in this study, the SGA group demonstrated a greater improvement in BMI at years 3, 4, and 5 than at pre-treatment levels, which suggested that GH treatment may have a more pronounced effect on body composition in this subgroup. However, in the combined GHD and SGA group, BMI significantly increased only during the first year of GH treatment and showed no further significant change thereafter. The absence of sustained significance is likely attributable to the limited statistical power arising from the relatively small subgroup size. Moreover, compared with that in the SGA-only group, the magnitude of BMI improvement in the GHD and SGA groups was small, suggesting that the metabolic response to GH treatment may differ according to the underlying growth disorder.

Beyond physical development, biochemical markers provide additional insights into the metabolic impact of the intervention. In all groups, the liver function parameters, AST and ALT, exhibited significant reduction over the treatment period, reaching normal levels. This finding supports previous evidence suggesting that GH may contribute to improved hepatic function (23, 24). These findings are consistent with those of prior research highlighting the role of GH and insulin-like growth factor 1 (IGF-1) in reducing hepatic inflammation, oxidative stress, and lipid accumulation, which are key contributors to liver dysfunction (25). As the liver is a primary target organ for GH and IGF-1, patients with GHD are at an increased risk of developing MASLD; both GHD and MASLD are recognized as major complications in adults with GHD (8). Additionally, rapid postnatal weight gain in children with SGA is associated with an increased risk of MASLD (26). The findings of this study suggest that appropriate GH treatment may help reduce complications such as MASLD, underscoring its potential role in metabolic health management.

Uric acid levels gradually increased during GH treatment in all three groups. This metabolic change has been observed in patients with idiopathic short stature, suggesting that it may be a common response to GH treatment (27). The increase in uric acid levels during GH treatment is likely due to enhanced purine metabolism driven by increased protein turnover and muscle mass expansion. GH stimulates anabolic processes, including muscle growth and tissue remodeling, which elevates nucleotide turnover and subsequently increases uric acid production (28). Additionally, GH influences renal function by modulating uric acid excretion, potentially contributing to its accumulation. Despite this increase, uric acid levels remained within the normal range, suggesting physiological adaptation rather than a pathological concern. Regular metabolic monitoring is recommended to ensure that uric acid levels do not exceed normal limits, particularly in patients with metabolic risk factors. In the present study, the greater increase in uric acid levels in the GHD group than in the SGA group may be attributed to a larger height increment. To further support this mechanistic interpretation, we conducted a correlation analysis and found that changes in uric acid levels were positively associated with BMI SDS during the first three years of treatment and with IGF-1 SDS across all time points in the GHD group, suggesting that uric acid elevation reflects GH-induced anabolic activity rather than adverse metabolic disturbance.

Lipid metabolism is another key area of interest, with total cholesterol levels exhibiting a downward trend. This observation aligns with previous findings (15, 29) suggesting that GH treatment may positively influence lipid profiles by affecting fat distribution and metabolic function in both the GHD and GHD–SGA groups (30). Another study reported a reduction in total cholesterol levels after GH treatment, along with an increase in high-density lipoprotein cholesterol levels (31). However, some studies have demonstrated no significant improvement in lipid profiles before and after treatment, possibly due to small sample sizes limiting statistical significance. Experimental work in healthy volunteers shows that a brief increase in GH activity intensifies adipose lipolysis, driving a ~25% rise in hepatic VLDL-TG export, thereby supplying circulation with additional triglyceride-rich particles (32). This substrate-driven secretion, together with the transient insulin resistance and reduced peripheral lipoprotein lipase activity observed during early GH exposure, offers a plausible biological explanation for the modest, non-significant TG elevation documented in the present study. Notably, the differences between the two study groups were minimal, indicating the broad applicability of these findings across various etiologies of growth impairment. However, because several lipid-related parameters were obtained in the non-fasting state, postprandial variability might have contributed to the modest and inconsistent changes observed, especially in TG levels.

Markers of glucose regulation exhibited transient elevation, particularly within the first year of treatment, but remained within the normal range. Consistent with earlier studies, GH acts as an insulin-counterregulatory hormone (33), increases insulin resistance, and can consequently affect glucose metabolism in both GHD and SGA. HbA1c levels increased slightly over the treatment period, with significant changes noted in the first and third years.; however, these changes remained within clinically acceptable limits. This suggests that although glucose metabolism is influenced by treatment (4), it does not necessarily predispose individuals to long-term dysregulation (34). Notably, despite previous reports indicating an increased risk of metabolic disorders, such as insulin resistance and diabetes, in the SGA group (13), no significant changes in HbA1c levels were observed. This indicates minimal adverse effects of GH treatment. However, continuous monitoring of glucose-related indices remains essential, particularly in populations predisposed to metabolic disturbances.

Although most metabolic indices remained within normal limits throughout the 5-year treatment period, the clinical relevance of these findings should be interpreted in light of established pediatric thresholds. In this study, none of the group means for glucose, triglycerides, uric acid, or liver enzymes exceeded conventional reference limits (e.g., AST or ALT > 40 U/L, uric acid > 6.0 mg/dL, Total cholesterol > 200mg/dL, TG > 150 mg/dL, glucose > 100 mg/dL). These results suggest that GH treatment exerts mild, physiological metabolic shifts rather than pathological changes. Nevertheless, we recommend periodic metabolic assessment ideally every 6–12 months with particular attention to glucose regulation, including fasting glucose and HbA1c, as GH treatment can transiently influence insulin sensitivity. Regular monitoring of uric acid is also advised, especially in patients with obesity, SGA, or other metabolic risk factors.

This study had some limitations. First, as this was a retrospective study, the number of available metabolic parameter measurements was limited, and missing data were sporadic, with differences in sample sizes among the GHD, SGA, and GHD–SGA subgroups. However, despite these limitations, the 5-year follow-up period and multicenter cohort design provide substantial value. Second, non-fasting blood samples were used for several metabolic indices, including glucose, TG, and cholesterol. This approach increased the sample size and enabled longitudinal comparisons, but may have introduced potential bias due to postprandial variability. Because fasting data were not consistently collected across all centers, a sensitivity analysis limited to fasting samples could not be performed. Future studies that focus exclusively on fasting levels may yield more precise metabolic insights.

In conclusion, this study highlights that hormonal intervention in pediatric patients with growth impairment is effective not only for promoting linear growth but also for optimizing metabolic health. The observed reduction in hepatic enzyme levels and improvement in lipid profiles suggest broader systemic benefits beyond height gains. However, careful monitoring of glucose metabolism and uric acid levels is essential to ensure the long-term safety of this intervention. Future research should focus on strategies to minimize potential metabolic risks while maximizing the positive effects of GH treatment.