Gamma-aminobutyric acid supplementation combined with gonadotropin-releasing hormone analog therapy versus gonadotropin-releasing hormone analog therapy alone for linear growth in children with growth retardation: a retrospective cohort study

Introduction

Background

Whether in cases of central precocious puberty (CPP) or early and fast puberty (EFP), early or accelerated puberty leads to an initial growth spurt followed by early closure of the epiphyseal plates, compromising the potential for adult height. CPP is defined as early activation of the hypothalamic-pituitary-gonadal (HPG) axis, leading to the appearance of secondary sexual characteristics before the age of 8 years in girls or 9 years in boys. It occurs in approximately 1 in 5,000 to 10,000 children, with a female-to-male ratio of 10:1 (1,2). EFP is characterized by the onset of puberty at the normal lower limit but with accelerated progression, and shares similar pathophysiological mechanisms and clinical consequences with CPP (3). Gonadotropin-releasing hormone (GnRH) analogues have become the standard treatment for both CPP and EFP, effectively suppressing gonadal steroid secretion and delaying the progression of puberty (4,5).

The primary goal of GnRH analog therapy is to prevent premature closure of the epiphysis, thereby improving adult final height. Although this treatment is successful in delaying skeletal maturation and improving predicted height in most patients, some individuals experience significant growth retardation, which may reduce the therapeutic benefit (6-8). Research indicates that younger children with CPP typically achieve greater height gain than those with EFP and show delayed epiphyseal closure after treatment discontinuation (9). However, growth retardation remains a significant challenge in all age groups receiving GnRH analog therapy.

The mechanisms underlying growth retardation during GnRH analog treatment are not fully understood. Evidence suggests that lowering estrogen levels below normal pre-pubertal levels may contribute to reduced growth velocity (GV) (10,11). In addition, changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis are a possible factor, with studies confirming reduced nocturnal GH secretion and decreased IGF-1 bioactivity during treatment (12,13). These physiological changes may result in growth rates falling below the 25th percentile for age-matched peers, limiting the potential for treatment-induced height gain (14).

Multiple intervention strategies have been explored to address growth retardation in children undergoing GnRH analog therapy, but each carries limitations detailed in the following section. Gamma-aminobutyric acid (GABA), as the main inhibitory neurotransmitter in the central nervous system, has emerged as a potential regulator of growth hormone secretion. Studies confirm that oral GABA supplementation raises plasma growth hormone levels in adults via dual central and peripheral mechanisms (15-17). Research shows that high-dose GABA (5 grams orally) significantly increases growth hormone levels, with its mechanism involving dopamine pathways in the pituitary gland (18,19). Although research on GABA supplementation in children remains limited, current evidence suggests controllable safety when used appropriately (4,20,21). International consensus statements, including those from the European Society for Paediatric Endocrinology (ESPE) and the American Academy of Pediatrics (AAP), currently recommend gonadotropin-releasing hormone agonist (GnRHa) as the standard treatment for CPP, but do not specify a preferred adjunct for associated growth retardation (4). An important theoretical consideration for GABA as a growth-promoting agent is its blood-brain barrier (BBB) permeability, which remains debated in the literature. While peripheral GABA may act via pituitary GABA_A receptors independent of CNS entry, the extent of its central action in children has not been established, and pediatric dosing for growth stimulation lacks formal guidelines.

Rationale and knowledge gap

Despite the theoretical basis and practical advantages of GABA supplementation, no studies have systematically evaluated its efficacy in children with GnRHa-related growth retardation. Current management strategies for this clinical challenge remain limited. Recombinant human growth hormone (rhGH) combination therapy, while effective in achieving 7–8 cm greater height gain compared to GnRHa monotherapy (22,23), requires daily subcutaneous injections, imposes significant financial burden, and is not universally accessible, particularly in resource-limited settings. Alternative interventions such as oxandrolone carry risks of virilization and potential acceleration of bone maturation (24), while low-dose estrogen supplementation requires careful monitoring to prevent puberty breakthrough (25). Aromatase inhibitors, although capable of delaying epiphyseal fusion, have uncertain long-term safety profiles (26).

GABA offers several theoretical advantages as an adjunctive therapy: it can be administered orally, is readily available as a nutritional supplement, has a favorable safety profile documented in adults (20,21), and operates through mechanisms distinct from gonadotropin suppression—potentially stimulating GH secretion via hypothalamic GABAergic neurons and direct pituitary GABA_A receptor activation (27,28). However, whether these GH-stimulating effects observed in adult studies translate into clinically meaningful growth improvements in children receiving GnRHa therapy, and whether such supplementation interferes with the primary therapeutic goal of HPG-axis suppression, remain unknown. Furthermore, it is unclear whether the benefits of GABA supplementation, if any, are consistent across different patient subgroups, including those with varying baseline growth velocities, IGF-1 levels, ages, or diagnostic categories (CPP vs. EFP). This study provides the first real-world clinical evidence in pediatric populations linking GABA supplementation with measurable growth outcomes, helping to bridge the gap between mechanistic findings and clinical applicability.

Objective

This study aims to address these knowledge gaps by evaluating the efficacy and safety of GABA supplementation in children with CPP or EFP who experience growth retardation during GnRHa treatment. The primary objective was to determine whether GABA supplementation improves height standard deviation score (HtSDS) over a 12-month treatment period compared to GnRHa therapy alone. Secondary objectives included evaluating the effects of GABA on GV across different time intervals (0–3, 3–6, and 6–12 months), predicted adult height (PAH), and safety outcomes including adverse events (AEs) and maintenance of HPG-axis suppression. Additionally, we conducted prespecified subgroup analyses to explore potential heterogeneity of treatment effects across sex, age, diagnosis, baseline GV, and baseline IGF-1 status.

A prospective randomized controlled trial would be ideal to evaluate GABA efficacy; however, given the ethical considerations of withholding a low-risk, freely available supplement in symptomatic children, the lack of prior pediatric efficacy data, and the exploratory nature of this question, a retrospective cohort design was selected as an appropriate first step. Therefore, findings should be interpreted as associative rather than causal. This approach allows evaluation of real-world effectiveness while informing the feasibility and sample size requirements for future RCTs. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0024/rc).

Methods

The screening, eligibility assessment, and cohort allocation are summarized in Figure 1. We reviewed the medical records of The First Affiliated Hospital of Ningbo University from January 1, 2020, to October 1, 2025. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Institutional Review Board of The First Affiliated Hospital of Ningbo University (ethical approval No. 2025199RS). Informed consent was waived due to the study’s retrospective nature, and all patient data were anonymized to maintain confidentiality throughout the research.

Figure 1 Flow diagram of research. Medical records (January 1, 2020 to October 1, 2025) were screened. Eligible participants were children with CPP or EFP receiving GnRHa therapy for at least 12 months, with adequate hormonal suppression (stimulated LH peak <3.0 mIU/mL) and growth retardation (growth velocity <5 cm/year). Exclusions included other conditions or medications affecting growth and inadequate treatment compliance. The final cohort comprised 150 children, allocated to GnRHa + GABA (n=99) or GnRHa alone (n=51). AE, adverse event; ANCOVA, analysis of covariance; BA, bone age; BMI, body mass index; CA, chronological age; CI, confidence interval; CPP, central precocious puberty; EFP, early and fast puberty; FSH, follicle-stimulating hormone; GABA, γ-aminobutyric acid; GnRHa, gonadotropin-releasing hormone agonist; GV, growth velocity; HtSDS, height standard deviation score; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; mo, months; PAH, predicted adult height; RR, relative risk; SD, standard deviation; SDS, standard deviation score.

We included consecutive patients who met our criteria during this time period, including children who received GnRHa for CPP or EFP and whose growth slowed despite good hormonal control. Specifically, (I) patients were required to have receivedregular GnRHa treatment for at least 12 months after enrollment. (II) Sufficient suppression (stimulation peak <3.0 mIU/mL). (III) Growth retardation, defined as annual GV <5 cm/year. (IV) Complete height measurements at multiple points in time. We excluded children with other conditions that affect growth, such as growth hormone deficiency or thyroid problems, drugs that could interfere with growth, and children who did not maintain hormone suppression during follow-up. Treatment compliance was assessed through two components: (I) product adherence compliance, evaluated by counting remaining GABA tablets at each scheduled clinic visit—a prospective monitoring protocol that had been routinely implemented for all patients prescribed nutritional supplements in our clinic since 2020—and calculating the percentage of prescribed doses consumed; and (II) follow-up compliance, defined as attendance at scheduled clinic visits. Participants with either product adherence or follow-up compliance <80% were considered dropouts and excluded from the final analysis. All 150 participants included in this study achieved ≥80% compliance for both measures. It is important to note that this is not a randomized trial. Group allocation was based on real-world clinical practice: physicians recommended GABA supplementation primarily when families expressed concerns about growth retardation but declined injectable therapies (rhGH), or when cost constraints precluded rhGH use. Families who accepted rhGH or declined all adjuncts formed the control group. This allocation process was documented in clinical notes and reviewed during data extraction. This non-random allocation introduces potential selection bias, particularly related to socioeconomic status, treatment preference, and caregiver decision-making. The main focus was on changes in height SDS over the 12-month period. They also tracked growth rates over various time periods (0–3, 3–6, and 6–12 months), predicted changes in adult height, hormone levels that confirmed persistent suppression, and side effects or AEs. Height was measured by a trained nurse using a standard wall-mounted rangefinder. Bone age (BA) is assessed by an experienced pediatric endocrinologist. Standard methods for the population were used to calculate the PAH. PAH was calculated using the Bayley-Pinneau method based on BA assessment from left hand and wrist radiographs evaluated according to the Greulich-Pyle atlas. PAH was derived from age- and sex-specific growth curves using the formula that incorporates current height, BA, and population-specific height prediction tables.

Statistical analysis

Welch t-test (which deals with unequal variance better than the standard t-test) was used to compare the two groups, and robustness was determined using ANCOVA corrected for baseline age, HtSDS, BA/chronological age (CA), sex, target height, GV, IGF-1, and GnRHa duration. Subgroup analyses were performed to identify potential effect regulators. A mixed-effect model is used for the pattern of growth rate over time. Subgroup analysis was prescribed in advance to explore the heterogeneity of treatment effects. For subgroup analyses, we used linear regression models with treatment × subgroup interaction terms. These regression-based conditional effects estimate treatment benefits while holding other covariates constant, which differs methodologically from the marginal mean differences reported in Table 2. The P interaction value tests whether the treatment effect significantly differs between subgroup levels.Interactions with treatment between sex, age (≥9.0 vs. <9.0 years), baseline growth rate (≥4.16 vs. <4.16 cm/year), baseline IGF-1 SDS (≥−1.0 vs. <−1.0), diagnosis (CPP vs. EFP), and the occurrence of AEs were examined. Cohen’s d was used to calculate the effect size and quantify the magnitude of difference between subgroups. All P values were based on two-sided testing, with statistical significance set at P<0.05. All analyses were performed using SPSS (version 26.0).

Results

Of 150 enrolled children, 99 received GnRHa + GABA, and 51 received GnRHa alone. The cohort was predominantly female (n=125, 83.3%) with a mean age of 9.0 years. Baseline characteristics were well-balanced between groups (Table 1). Both groups demonstrated significant growth deceleration at enrollment, with mean GV of 4.16±0.48 cm/year, representing a decline from pre-treatment growth patterns. Mean height SDS was 0.13±0.30 in the GABA group and 0.13±0.28 in controls (P=0.95). BA advancement was comparable (BA/CA ratio: 1.05±0.06 vs. 1.05±0.06, P=0.88), as were target heights (163.29±5.99 vs. 161.95±5.99 cm, P=0.11). Hormonal parameters confirmed adequate suppression in both groups, with GnRH-stimulated luteinizing hormone (LH) peak <3.0 mIU/mL in all participants. Mean duration of prior GnRHa therapy was similar between groups (18.5±6.2 vs. 17.8±5.9 months, P=0.42) (Table 1).

At 12 months, the GnRHa + GABA group demonstrated significantly greater improvement in height SDS compared to controls [ΔHtSDS: 0.53±0.22 vs. 0.05±0.12; mean difference 0.48, 95% confidence interval (CI): 0.43–0.53, P<0.001], Cohen’s d =2.50. This difference remained significant after adjusting for baseline covariates [adjusted difference 0.48 (0.43, 0.53), P<0.001], indicating a large treatment effect. During months 0–3, GV was 4.15±0.48 cm/year in the GnRHa + GABA group and 4.16±0.48 cm/year in controls (P=0.90). GV was higher with GABA during months 3–6 (4.79±0.53 vs. 4.18±0.48; P<0.001) and 6–12 (5.98±0.64 vs. 4.19±0.49; P<0.001), demonstrating sustained efficacy. PAH showed greater improvement in the GABA group (ΔPAH: 3.00 ±0.71 vs. 0.25±0.51 cm; difference 2.75 cm; 95% CI: 2.55–2.95, P<0.001). IGF-1 SDS remained stable in both groups (−0.00±0.57 vs. −0.07±0.63, P=0.54), suggesting the growth improvement was not mediated by changes in systemic IGF-1 levels. AE rates were similar between groups (22.2% vs. 17.6%, P=0.67). A total of 42 AEs were reported among 31 participants (22 in the GnRHa + GABA group, nine in the GnRHa group). All AEs were mild and self-limiting. The most common AEs were gastrointestinal symptoms (abdominal discomfort and nausea; n=17, 40.5%), followed by neurological symptoms (somnolence and dizziness; n=13, 31.0%), skin reactions (rash; n=6, 14.3%), and injection site pain (n=6, 14.3%). No serious AEs requiring treatment discontinuation or hospitalization occurred in either group. Hormonal suppression was maintained throughout follow-up. At 12 months, GnRH-stimulated LH peak remained <3.0 mIU/mL in both sexes (Table S1), indicating sustained HPG-axis suppression. (Table S1), confirming no interference with GnRHa efficacy (Table 2, Figures 2A-5A).

Figure 2 (A) Comparison of HtSDS; between GnRHa + GABA and GnRHa groups after 12 months of treatment. ΔHtSDS after 12 months of treatment. (A) Box plots show ΔHtSDS from baseline to 12 months in the GnRHa + GABA group (n=99) and the GnRHa group (n=51). ΔHtSDS was 0.53±0.22 vs. 0.05±0.12, respectively (mean difference 0.48; 95% CI: 0.43–0.53; P<0.001; Welch’s t-test). Boxes represent the IQR; center lines, medians; whiskers, 1.5× IQR; dots, individual observations. ***, P<0.001. (B) Subgroup analysis of ΔHtSDS at 12 months. Forest plots display the treatment effect (mean difference between GnRHa + GABA group and GnRHa alone group) with 95% CIs (error bars) for each subgroup level. Blue squares indicate level 0 of each subgroup variable (female, <9 years, CPP, <4.16 cm/year baseline GV, <−1.0 SDS baseline IGF-1, no adverse events), and red squares indicate level 1 (male, ≥9 years, EFP, ≥4.16 cm/year, ≥−1.0 SDS, yes adverse events). The vertical dashed line represents the null effect (no treatment difference). P interaction values (shown to the right of each subgroup) were derived from linear regression models including treatment × subgroup interaction terms, testing whether treatment effects differed significantly between subgroup levels. P interaction <0.05 (shown in red) indicates statistically significant heterogeneity of treatment effect across subgroup levels. Horizontal bars indicate 95% CIs; the vertical line denotes no difference. Exact effect sizes with 95% CIs and subgroup definitions are summarized in Table 3. AE ≥1: adverse event incidence ≥1 times. AE, adverse event; CI, confidence interval; CPP, central precocious puberty; EFP, early and fast puberty; GABA, γ-aminobutyric acid; GnRHa, gonadotropin-releasing hormone agonist; GV, growth velocity; IGF-1, insulin-like growth factor-1; IQR, interquartile range; SDS, standard deviation score; ΔHtSDS, change in height standard deviation score.

Figure 5 (A) Comparison of the incidence of any AE between groups. The bar graph shows the proportion of patients who experienced ≥1 AE) during treatment in the GnRHa + GABA group (n=99) and the GnRHa group (n=51). The incidence of any AE was 22.2%, 22/99 in the GnRHa + GABA group and 17.6%, 9/51 in the GnRHa group. The RR was 1.26 [95% CI: 0.63–2.53], P=0.67; χ² test. (B) Subgroup analysis of change adverse events. Forest plots display the treatment effect (mean difference between GnRHa + GABA group and GnRHa alone group) with 95% CIs (error bars) for each subgroup level. Blue squares indicate level 0 of each subgroup variable (female, <9 years, CPP, <4.16 cm/year baseline GV, <−1.0 SDS baseline IGF-1, no adverse events), and red squares indicate level 1 (male, ≥9 years, EFP, ≥4.16 cm/year, ≥−1.0 SDS). The vertical dashed line represents the null effect (no treatment difference). P interaction values (shown to the right of each subgroup) were derived from linear regression models including treatment × subgroup interaction terms, testing whether treatment effects differed significantly between subgroup levels. P interaction <0.05 (shown in red) indicates statistically significant heterogeneity of treatment effect across subgroup levels. the vertical line denotes no difference. Exact effect sizes with 95% CIs and subgroup definitions are summarized in Table 3. AE, adverse event; CI, confidence interval; CPP, central precocious puberty; EFP, early and fast puberty; GABA, γ-aminobutyric acid; GnRHa, gonadotropin-releasing hormone agonist; GV, growth velocity; IGF-1, insulin-like growth factor-1; NS, not significant; SDS, standard deviation score.

To evaluate whether treatment effects varied across patient subgroups, we performed treatment × subgroup interaction analyses using linear regression models with interaction terms. Treatment effects (mean difference in outcomes between GnRHa + GABA and GnRHa alone groups) were estimated within each subgroup level with 95% CIs. For the primary outcome (ΔHtSDS at 12 months), GABA supplementation demonstrated consistent beneficial effects across all pre-specified subgroups. Treatment effects were significant in both sexes [female: 0.184 (95% CI: 0.140–0.229); male: 0.127 (95% CI: 0.042–0.211); P interaction=0.41], age groups [<9 years: 0.165 (95% CI: 0.108–0.222); ≥9 years: 0.202 (95% CI: 0.144–0.261); P interaction=0.42], diagnostic categories [CPP: 0.199 (95% CI: 0.147–0.251); EFP: 0.157 (95% CI: 0.091–0.223); P interaction =0.38], baseline GV groups [<4.16 cm/year: 0.207 (95% CI: 0.148–0.266); ≥4.16 cm/year: 0.155 (95% CI: 0.099–0.210); P interaction=0.25], baseline IGF-1 levels [<−1.0 SDS: 0.193 (95% CI: 0.091–0.294); ≥−1.0 SDS: 0.181 (95% CI: 0.137–0.226); P interaction=0.86], and regardless of AE occurrence [no AE: 0.174 (95% CI: 0.127–0.220); yes AE: 0.218 (95% CI: 0.132–0.304); P interaction=0.44]. For the primary outcome (ΔHtSDS at 12 months), treatment effects were consistent across prespecified subgroups with no significant treatment-by-subgroup interactions (all P interaction>0.05; Table 3). For secondary outcomes, interactions were also generally non-significant; however, a nominal interaction was observed for 6–12 months GV by AE occurrence (P interaction=0.02), with larger GV gains in participants without AEs (Figures 2B,3B,3C,4B,5B, Table 3).

Figure 3 (A) Comparison of GV between GnRHa + GABA and GnRHa groups during different treatment periods GV was similar during months 0–3 (4.15±0.48 vs. 4.16±0.48; P=0.90) but higher with GABA during months 3–6 (4.79±0.53 vs. 4.18±0.48; P<0.001) and months 6–12 (5.98±0.64 vs. 4.19±0.49; P<0.001) (Welch’s t-test). Shaded areas represent 95% confidence intervals. (B-D) Subgroup analysis of change in growth velocity during months 0–3, 3–6, 6–12 (cm/year). Forest plots display the treatment effect (mean difference between GnRHa + GABA group and GnRHa alone group) with 95% confidence intervals (error bars) for each subgroup level. Blue squares indicate level 0 of each subgroup variable (female, <9 years, CPP, <4.16 cm/year baseline GV, <−1.0 SDS baseline IGF-1, no adverse events), and red squares indicate level 1 (male, ≥9 years, EFP, ≥4.16 cm/year, ≥−1.0 SDS, yes adverse events). The vertical dashed line represents the null effect (no treatment difference). P interaction values (shown to the right of each subgroup) were derived from linear regression models including treatment × subgroup interaction terms, testing whether treatment effects differed significantly between subgroup levels. P interaction <0.05 (shown in red) indicates statistically significant heterogeneity of treatment effect across subgroup levels. CI, confidence interval; CPP, central precocious puberty; EFP, early and fast puberty; GABA, γ-aminobutyric acid; GnRHa, gonadotropin-releasing hormone agonist; GV, growth velocity; IGF-1, insulin-like growth factor-1; SDS, standard deviation score.

Figure 4 (A) ΔPAH over 12 months between groups. Box-and-whisker plots show the 12-month ΔPAH (cm) from baseline in patients treated with GnRHa + GABA (n=99) and GnRHa alone (n=51). Mean ± SD of ΔPAH were 3.00±0.71 and 0.25±0.51 cm, respectively. The mean difference between groups was 2.75 cm (95% CI: 2.55–2.95; P<0.001; Welch’s t-test). ***, P<0.001. (B) Subgroup analysis of ΔPAH (cm) at 12 months. Forest plots display the treatment effect (mean difference between GnRHa + GABA group and GnRHa alone group) with 95% CIs (error bars) for each subgroup level. Blue squares indicate level 0 of each subgroup variable (female, <9 years, CPP, <4.16 cm/year baseline GV, <−1.0 SDS baseline IGF-1, No adverse events), and red squares indicate level 1 (male, ≥9 years, EFP, ≥4.16 cm/year, ≥−1.0 SDS, yes adverse events). The vertical dashed line represents the null effect (no treatment difference). P interaction values (shown to the right of each subgroup) were derived from linear regression models including treatment × subgroup interaction terms, testing whether treatment effects differed significantly between subgroup levels. P interaction <0.05 (shown in red) indicates statistically significant heterogeneity of treatment effect across subgroup levels. Horizontal bars indicate 95% CIs; the vertical line denotes no difference. Exact effect sizes with 95% CIs and subgroup definitions are summarized in Table 3. ΔPAH, changes in predicted adult height; CI, confidence interval; CPP, central precocious puberty; EFP, early and fast puberty; GABA, γ-aminobutyric acid; GnRHa, gonadotropin-releasing hormone agonist; GV, growth velocity; IGF-1, insulin-like growth factor-1; mo, months; SD, standard deviation; SDS, standard deviation score.

Similar patterns were observed for secondary outcomes. For ΔPAH, treatment effects remained consistent across all subgroups (all P interaction>0.05), with mean improvements ranging from 0.509 to 0.998 cm. GV improvements at 6–12 months were also uniform across most subgroups, although a nominally significant interaction was observed for AEs (P interaction=0.02), with patients without AEs showing slightly larger GV improvements (1.316 vs. 0.792 cm/year). However, treatment effects remained significant in both subgroups (both P<0.001).

Importantly, treatment × age interaction analysis revealed no significant heterogeneity for any outcome, suggesting that GABA supplementation is equally effective in children with classical CPP (<9 years) and those with EFP (≥9 years). Similarly, the treatment benefit was not modified by baseline GV or IGF-1 status, indicating that patients with more severe growth retardation at baseline derive similar relative benefits from GABA supplementation.

Discussion

Key findings

This real-world study showed that GABA supplements combined with GnRH analog therapy resulted in a gradual but clinically significant improvement in growth parameters in a growth slowdown of children with CPP and EFP. The addition of GABA increased SDS changes in height by 0.48 SDS within 12 months and predicted a 2.75cm increase in adult height, without affecting hormone suppression, promotion of epiphyseal fusion, or increased AEs.

Strengths and limitations

GABA supplements may have several practical benefits compared to other strategies to manage growth slowdown. Although the rhGH combination therapy resulted in greater height gain (7–8 vs. 2.75 cm) (22,23), GABA was very readily available; only oral administration was required, and the cost was significantly reduced. The safety profile in this cohort was favorable, with no significant increase in AEs compared to GnRH analog monotherapy. This is in contrast to oxandrolone, which carries the risk of virilization and potential acceleration of bone maturation, and low-dose estrogen supplementation, which requires careful monitoring to avoid puberty breakthrough. In addition, unlike aromatase inhibitors, which delay epiphyseal fusion but have uncertain long-term effects, GABA has a good safety profile. There are a few limitations that are worth considering. The retrospective design and lack of randomization introduced a potential selection bias. Additionally, as a single-center study, our findings may have limited generalizability to other regions or populations. The control group’s refusal to supplement GABA may reflect unmeasurable differences in disease severity and family characteristics. We also did not measure the detailed dynamics of GH or IGF-1 during treatment, which limited our knowledge of the mechanism. A follow-up period of 12 months was sufficient to demonstrate a lasting effect, but could not predict long-term outcomes or ultimate adult height. Residual confounding cannot be excluded despite statistical adjustment, and causal inference should be interpreted with caution.

Comparison with similar research

Our cohort, which includes children with true CPP (onset before age 8 years) and EFP (onset between age 8–9 years), reflects real-world clinical practice where they can benefit from treatment to prevent early epiphyseal fusion/epiphyseal closure (9). Previous studies have shown that compared to children with early-onset CPP, children with EFP have less increase in height in children with GnRH analogue therapy because they have already experienced puberty progression and bone maturation (29). Our research shows that the consistent benefits of GABA supplements across all age groups are useful regardless of age at the start of puberty.

Explanations of findings

The growth improvements observed with GABA supplements are consistent with the known effects on GH secretion. Previous studies have confirmed that oral administration of GABA can acutely increase plasma GH levels in adults (15,16). Our findings suggest that the GH-stimulating effect of GABA may partially offset the growth-inhibiting effect of GnRH analogs, and that sustained improvement in growth rate without accelerating BA progression over all measured time periods suggests that GABA promotes linear growth without accelerating osteogenic fusion.

During puberty, growth hormone (GH) secretion is influenced by multiple factors. Sex steroids, particularly estrogen, play a crucial role in modulating GH secretion through both hypothalamic and pituitary mechanisms. GnRHa therapy suppresses gonadal steroid production, which may consequently reduce the physiological enhancement of GH secretion typically observed during puberty (12,13). Additionally, nutritional status, sleep quality, and physical activity also influence GH pulsatility during this developmental period.

GABA may counteract GnRHa-induced growth retardation through several specific mechanisms. First, GABA stimulates GH release via GABAergic neurons in the hypothalamus that modulate growth hormone-releasing hormone (GHRH) secretion (27). Second, GABA can act directly at the pituitary level via GABA_A receptors, producing depolarization and Ca²⁺ entry that is permissive for hormone secretion, including GH (28). Third, studies have demonstrated that GABA’s effect on GH secretion involves dopaminergic pathways, as evidenced by the attenuation of GABA-induced GH rise by dopamine receptor antagonists (18). This dual central-peripheral mechanism may explain why GABA supplementation effectively improves growth outcomes without interfering with the gonadotropin-suppressing effects of GnRHa therapy.

The maintenance of normal BA progression was particularly pronounced in the GABA treatment group. Unlike some adjuvant therapies that promote bone maturation, GABA supplementation maintains an appropriate BA early (BA/CA ratio remains stable) and suggests that it promotes growth without affecting delayed epiphyseal fusion, the main goal of GnRH analogue therapy. This finding is important to ensure that short-term growth improvements lead to meaningful growth in eventual adult height (30).

Subgroup analysis provides insight into the patients who benefit most from GABA supplements. The consistent effects between gender, age group (including CPP and EFP), and baseline growth rates indicate broad applicability. However, the increasing trend of benefit in children with low baseline IGF-1 levels deserves further study, as it may identify a particularly sensitive subgroup.

Implications and actions needed

The clinical significance of these results should be carefully examined. While the increase in height with GABA supplements is modest compared to rhGH, it makes sense for families looking to optimize growth outcomes without the burden of injectable therapy. GABA is particularly valuable in resource-limited settings and in families who cannot afford rhGH. Its excellent safety and oral administration make it a practical supplement for CPP treatment devices.

Conclusions

Adding GABA supplements to GnRHa treatment significantly improves growth outcomes in children with CPP and EFP, especially those experiencing growth slowdown. Treatment with GABA resulted in a significant increase in growth rate, and consistent effects were observed throughout the treatment period. These improvements were achieved without significant side effects or interference with puberty suppression. GABA supplementation may represent a promising, safe, and cost-effective adjunctive option for improving growth outcomes in children receiving GnRHa therapy. Besides, these benefits were consistent across patient subgroups, supporting the broad applicability of GABA supplementation in children receiving GnRHa therapy. These results support the view of GABA as a valuable addition to treatment programs for children with CPP or EFP who are suffering from growth slowdown during GnRHa treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0024/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0024/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0024/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0024/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 Institutional Review Board of The First Affiliated Hospital of Ningbo University (ethical approval No. 2025199RS). Informed consent was waived due to the study’s retrospective nature, and all patient data were anonymized to maintain confidentiality throughout the research.

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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