Idiopathic short stature (ISS) in boys is an important clinical concern owing to the psychosocial impact of short stature and the limitations of growth hormone (GH) monotherapy in cases of rapidly advancing bone age [1] [2] . Aromatase inhibitors (AIs) have been proposed as adjuvant treatments that can inhibit estrogen production to delay bone maturation and extend the growth period [2] - [4] .

P450 aromatase is a key enzyme in converting C19 androgens (androstenedione and testosterone) to C18 estrogens (estrone and estradiol) [5] . In males, testicular aromatase contributes to only a small proportion (approximately 15%) of circulating estrogens, while extragonadal tissues, e.g., bone, brain, and adipose tissue, play a critical role in local estrogen synthesis [6] [7] . This extragonadal estrogen production acts mainly through paracrine and intracrine mechanisms, regulating skeletal maturation and epiphyseal fusion [8] [9] .

The importance of estrogen in male bone development is evident in cases where delayed closure of the epiphysis and large final elongation are observed in patients with estrogen receptor gene mutations or aromatase deficiency [10] [11] . Conversely, rapid progression of bone age and low final elongation have been reported in cases of aromatase excess syndrome, suggesting that estrogen plays a decisive role in bone maturation [12] . Based on this mechanism, AIs have been proposed as adjuncts to GH therapy to suppress estrogen production, delay bone maturation, and prolong the growth period in boys with ISS.

Several clinical studies have reported the effects of AI on height increase in boys with ISS [13] - [15] . In one randomized placebo-controlled study, when letrozole was administered for 2 years, the progression of bone age was significantly suppressed and the predicted final height increased by 5.9 cm, with no negative effect on bone density [16] . In another study, the combination of GH and AI showed better height increase and improvement in body composition change than GH alone or AI alone [17] . However, concerns remain regarding potential adverse effects, including glucose intolerance, hematologic changes, acne, and liver function abnormalities, which warrant careful evaluation in clinical practice [18] - [20] .

Most existing studies on the use of AIs in patients with ISS have been conducted in Western populations. Thus, clinical data from Asian patients, particularly Korean children, remain limited. In Korea, the use of AIs for ISS is not officially approved, and clinicians often hesitate to use this treatment owing to the absence of evidence in Asians. Therefore, this study aimed to evaluate the short-term efficacy and safety of combined GH and AI therapy in Korean boys with ISS and its effect on advanced bone age, with the goal of providing the first clinical evidence for this treatment approach in an Asian population.

A total of 35 boys with ISS were included in this study, with 8 in the GH-only group and 27 in the GH + AI group. Compared with the GH-only group, the GH + AI group had significantly more advanced bone age at the start of treatment (15.99 ± 1.06 years versus [vs.] 12.38 ± 0.83 years), and their chronological age and height were higher ( Table 1 ).

SD, standard deviation; GH, growth hormone; AI, aromatase inhibitor.

Despite these less favorable baseline characteristics, the GH + AI group achieved an annual growth velocity of 5.21 ± 1.61 cm/year, which was statistically lower than that in the GH-only group (10.25 ± 2.54 cm/year, p = 0.001) but still clinically meaningful, as reflected by the greater improvement in height SDS compared with the GH-only group ( Table 2 , Figure 1 and Figure 2 ). Additionally, the GH + AI group demonstrated a significantly lower ΔBA/CA ratio than the GH-only group (0.11 ± 0.25 vs. 0.55 ± 0.64, p = 0.046), indicating effective deceleration of bone maturation through aromatase inhibition ( Figure 3 ).

IGF-1 and IGF-BP3 levels increased significantly in both groups during treatment. At the end of the treatment period, the IGF-1 level was significantly higher in the GH + AI group than in the GH-only group (728.08 ± 143.45 ng/mL vs. 343.00 ± 67.28 ng/mL, p = 0.002). HbA1c levels remained stable in both groups throughout the treatment period.

GH, growth hormone; AI, aromatase inhibitor; SDS, standard deviation score; IGF-1, insulin-like growth factor 1; IGF-BP3, insulin-like growth factor-binding protein 3; HbA1c, glycated hemoglobin.

Adverse events were mild and included acne and hair loss ( Table 3 ). None of the participants discontinued treatment due to side effects, and the overall incidence of adverse reactions did not differ significantly between the groups (all p > 0.05).

To further explore the clinical importance of bone age suppression, individual response analysis showed that 20 out of 27 patients (74.1%) in the GH + AI group exhibited a ΔBA/CA ratio below 0.2. Although the GH + AI group showed a numerically higher frequency of acne than the GH-only group (44.4% vs. 25.0%), no serious dermatologic or systemic adverse events were observed, and all patients completed the treatment protocol.

GH, growth hormone; AI, aromatase inhibitor.

This study demonstrated that the combination of AI and GH therapy was effective and well tolerated without major adverse effects in Korean boys with ISS and advanced bone age. Although the annual growth velocity in the GH + AI group was lower than that in the GH-only group, the observed growth was clinically meaningful, as reflected by a greater improvement in height SDS and a significant reduction in bone age progression (ΔBA/CA). These findings support the hypothesis that AIs can delay epiphyseal fusion and extend the growth period in boys during late puberty [21] - [24] . These findings may serve as practical evidence for clinicians making treatment decisions in this specific population.

GnRH analog (GnRHa) and GH combination therapy has also been reported to be effective in increasing height in some studies, but the results were inconsistent [25] - [28] . In particular, GnRHa treatment effectively delays bone fusion but can cause a state of decreased gonad function at an important time of puberty, which may negatively affect physical and psychosocial development [29] [30] .

The key mechanism underlying the effect of AIs is the suppression of estrogen biosynthesis. Estrogen is the primary regulator of epiphyseal closure in both sexes, as evidenced by males with aromatase deficiency or estrogen receptor mutations who demonstrate continued linear growth and delayed skeletal maturation despite normal or elevated androgen levels [10] [11] . By inhibiting aromatase activity, AIs block the conversion of androgens to estrogens, reducing estrogen-mediated chondrocyte senescence and apoptosis at the growth plate [8] [16] . This mechanism allows for continued proliferation and hypertrophy of chondrocytes, prolonging linear growth during late puberty when the window for height gain is limited [3] .

Previous studies support the use of AIs in boys with ISS. Hero et al. reported that letrozole administration in adolescent boys with ISS delayed bone maturation and increased predicted adult height by 5.9 cm over 2 years [16] . Similarly, Mauras et al. reported that 24 - 36 months of combined AI and GH therapy resulted in greater height gains than either treatment alone, with the AI + GH group showing an absolute increase of 22.5 cm compared with 20.6 cm in the GH group and 18.2 cm in the AI group [17] . Anastrozole use over 3 years in GH-treated boys also demonstrated sustained improvements in predicted adult height in a multicenter placebo-controlled trial [14] . Beyond ISS, clinical studies have shown that letrozole monotherapy in boys with constitutional delay of puberty significantly increases predicted or near-final adult height, supporting broader applicability of AIs in pubertal growth modulation [31] .

Despite these positive results, there are still concerns about long-term safety and off-label use in children. AIs are not officially licensed drugs for height growth purposes, and there is a high legal and ethical burden [32] . Domestic academia, including the Korean Society of Pediatric Endocrionology, is taking a cautious approach to AI use. While clinical studies have not established long-term reproductive risks, theoretical concerns based on hormonal modulation suggest the need for close follow-up, particularly in pubertal patients. Furthermore, prescribing off-label drugs represents a substantial burden for physicians [33] . However, in late pubertal boys with advanced bone age, GH alone is often ineffective, making AI + GH combination therapy the only viable option for achieving meaningful height gains. Families in this study strongly desired such therapy, recognizing that being below average height imposes not only cosmetic concerns but also profound emotional and social impacts. To protect patients and physicians, broader discussions and the development of policies supporting the safe and effective use of off-label therapies are urgently needed.

In this study, the annual growth rate in the GH + AI group was lower than that in the GH-only group, but this is attributable to the advanced bone age and limited growth capacity at baseline in the combined group. Nevertheless, the reduced ΔBA/CA in the GH + AI group suggests a potential for greater cumulative height gain over time if treatment is continued. Elevated IGF-1 and IGFBP-3 levels observed at the end of therapy further indicate that GH dosing was effectively titrated to support growth in these patients. Although the differences in IGF-1 and IGFBP-3 levels between groups may reflect relatively higher GH exposure in older, more skeletally mature patients, aromatase inhibition itself can also elevate IGF-1 levels by reducing estrogen-mediated suppression of hepatic IGF-1 synthesis. Thus, the observed increase in IGF-1 is likely due to a combination of both factors rather than GH dosing alone. However, elevated IGF-1 levels should be interpreted cautiously given their potential association with adverse outcomes.

This study has some limitations. The retrospective design and small sample size limit the generalizability of our findings. Additionally, the short treatment duration precludes assessment of final adult height. While prior prospective studies suggest potential benefits on predicted adult height, long-term data on actual attained height remain scarce.

This study suggests that combined treatment with growth hormone and an aromatase inhibitor can slow bone maturation and support linear growth in Korean boys with idiopathic short stature and advanced bone age. Such therapy may be considered in late-pubertal patients with limited growth potential, where growth hormone alone is often insufficient. Because aromatase inhibitors are used off-label and long-term safety data are lacking, treatment should be restricted to carefully selected patients and undertaken with close monitoring of pubertal progression, bone health, and metabolic status. Ethical and legal concerns may also limit clinical application, highlighting the need for clearer guidance and supportive policy. Larger prospective studies are required to confirm these findings and to assess final adult height and long-term safety.

We would like to acknowledge Editage for English language editing.