In this study, the height gain, which is the difference between FAH and PAH at the start of treatment, was significantly higher in the GnRHa + GH group compared to the GnRHa group in girls with central precocious puberty.
GnRHa is a standard treatment for central precocious puberty in both boys and girls. It is known to suppress the secretion of sex hormones to slow puberty and suppress rapid bone fusion to achieve FAH within the TH range [15, 16]. However, several studies have reported that GnRHa can reduce the growth velocity below the normal range suitable for age [7, 17, 18]. Studies on changes in the GH-IGF-1 axis during GnRHa treatment have been conducted; although no consensus has been reached, some studies have reported that a decrease in the biologically active IGF-1 level contributes to the subnormal growth velocity [8, 10, 19, 20]. Therefore, in the current clinical trial, if the PAH was small or the growth rate showed a noticeable reduction during GnRHa treatment, GH combination treatment was used to improve FAH.
In a previous study that analyzed factors affecting the subnormal growth velocity during GnRHa treatment in 50 girls with idiopathic central precocious puberty [21], the average age when subnormal growth velocity appeared was 9.9 years. In addition, the third year of GnRHa treatment carried the highest risk of subnormal growth velocity. There was a significant negative correlation with growth velocity SDS in the third and fourth years of treatment with BA at diagnosis. In our study, CA and BA at the start of GnRHa + GH treatment were 8.34 ± 0.44 years and 10.51 ± 0.91 years, respectively, which were older than those in the GnRHa group; however, there was no significant difference. Furthermore, the Tanner stage of the breast and pubic hair at the beginning of treatment showed no significant difference between the groups.
A study on 448 Chinese children with central precocious puberty and early puberty divided participants into a control group (n = 118), GnRHa monotherapy group (n = 276), and combination therapy group (n = 54). In the combination therapy group, the height gain (FAH − initial PAH) and genetic height gain were 9.51 ± 0.53 cm and 4.00 ± 0.05 cm, respectively, which were significantly higher than those in the other groups [22]. In addition, when compared according to the GH treatment period in the combination therapy group, the height gain was significantly higher in the group starting after 6–12 months than in the group starting GH therapy at the same time as GnRHa treatment. Furthermore, in a meta-analysis published in China, the GH combination treatment significantly improved the height, PAH, and height SDS − BA. In addition, when the starting age of GH treatment was less than 10 years and the GH treatment period was 12 months or more, a significant improvement was confirmed in height, PAH, and height SDS − BA [11].
In a previous study conducted of 20 girls with idiopathic central precocious puberty who received GnRHa monotherapy and GnRHa + GH treatment, pretreatment PAH and FAH were 155.5 ± 1.7 cm and 157.1 ± 2.5 cm, respectively, in patients treated with GnRHa alone. In the GnRHa + GH treatment group, pretreatment PAH was 152.7 ± 1.7 cm and FAH was 160.6 ± 1.3 cm. The height gain in the two groups was different, at 7.9 ± 1.1 cm and 1.6 ± 1.2 cm, respectively, which was significantly higher in combination treatment groups (P < 0.001) [23]. In a study of 35 girls with central precocious puberty published in Italy, the pretreatment PAH and FAH were 153.2 ± 5.0 cm and 161.2 ± 4.8 cm, respectively, in those treated with GnRHa + GH. In the groups treated with GnRHa alone, pretreatment PAH and FAH were 153.9 ± 3.8 cm and 156.6 ± 5.7 cm, respectively. The height gain when treated with GnRHa + GH was 12.7 ± 4.8 cm, which was higher than that in the GnRHa group, 2.3 ± 2.9 cm [24]. In the current study, the duration of GH treatment was 2.04 ± 0.90 years and the period between GnRHa and GH treatment was 6.59 ± 7.77 months. The height gain (FAH − initial PAH) was 9.22 ± 6.03 cm in patients treated with GnRHa + GH, which was significantly higher than the 4.72 ± 5.01 cm in those treated with GnRHa alone (P < 0.001). The ΔPAH in the GnRHa + GH group was 13.66 ± 6.39 cm, which was significantly higher than the GnRHa group (P = 0.005). This indicates a large progression in PAH in the combination treatment group and an improvement of height potential with GnRHa + GH treatment.
Previous studies showed that young CA at the time of diagnosis, height, height SDS, and PAH at the start and end treatment influence FAH after GnRHa monotherapy in girls with central precocious puberty [6, 25–27]. However, studies on factors affecting FAH in GnRHa + GH treatment in central precocious puberty are scarce. Moreover, there is no study reported in Korea. GH itself can certainly be a variable contributing to height gain, but in order to analyze the effect on gain in FAH according to GH dose and duration of treatment, we conducted this analysis. As a result, in this study, the factors influencing height gain in girls treated with GnRHa + GH were the PAH and BA at start of treatment. Contrary to expectations, GH treatment periods and dose were not identified as factors affecting gain in FAH; however, there is the limitation of a small sample size in this study.
The current study had several limitations. First, this study was a retrospective single-center study; therefore, further large prospective studies are required. Second, the sample size was relatively small. Thus, our findings are limited to this study population.
In conclusion, this study demonstrated the GnRHa + GH treatment is effective for girls with central precocious puberty. The gain in the FAH compared to PAH at the start of treatment was significantly higher with GnRHa + GH treatment when compared with GnRHa monotherapy.