Central precocious puberty (CPP) occurs when the hypothalamic-pituitary-gonadal (HPG) axis is activated prematurely in girls who are younger than 8 years old [1]. While multiple variables can contribute to CPP, its underlying cause generally remains unknown [1,2]. Significantly, instances of unknown cause are significantly more common in girls, accounting up approximately 90% of cases [2]. A variety of consequences have been associated to the diagnosis of CPP in girls, including early menarche, low adult height as a result of early epiphyseal fusion, and adverse psychological impacts [1]. Therefore, it is crucial to provide appropriate therapy to girls with CPP for the purpose to reduce these negative consequences.

The cornerstone of treatment for CPP is the administration of GnRH agonist [3]. By persistently attaching to pituitary GnRH receptors, these analogues suppress gonadotropin production and prevent pubertal activation. The process involves the downregulation of GnRH receptors, which in effect leads to the suppression of the HPG axis [4,5]. The following are the key elements of a successful therapy: delay the progression of bone age (BA), reduce growth velocity, regress pubertal development, and increase final adult height [3,6 7].

Currently, there are a variety of GnRH analogue formulations on the market. The 3month depot formulation has been recognized for its effectiveness in suppressing the pituitary-gonadal axis and pubertal development [8-10]. Leuprolide acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analogue is more potent than the natural hormone, which is composed of a biodegradable polymer that is dissolved in a biocompatible liquid solvent to form a liquid gel. The drug is released from this leuprolide depot as it biodegrades over time, enabling the continuous administration of leuprolide acetate. The lyophilized microsphere (10–30 mm) drug delivery systems were employed in the earlier depot formulations of leuprolide. In biodegradable form, leuprolide microspheres contain the active compound. 3-month leuprolide acetate has been approved for CPP in Thailand since 2017. The synthetic GnRH analogue triptorelin pamoate is characterized by the substitution of D-tryptophan for L-glycine at the sixth position. This alteration expands the plasma half-life and increases effectiveness by improving resistance to enzymatic degradation and affinity for the pituitary receptor. Since 2019, 3-month triptorelin has been approved for CPP in Thailand. However, there is a lack of comparative studies that evaluate the effectiveness of various formulations, specifically with regard to treatment completion.

This study investigates the results of treating Thai girls with CPP with 3-month intramuscular injections of leuprolide acetate (11.25 mg) versus 3-month intramuscular injections of triptorelin pamoate (11.25 mg). The aim is to evaluate the effectiveness of these treatments in suppressing LH levels after 6 months and assessing PAH at the end of the treatment.

The study involved a cohort of 116 girl participants, of which 71 received a 3-month treatment of leuprolide acetate 11.25 mg, while the remaining 45 participants received a treatment of 3-month triptorelin pamoate 11.25 mg. Initial clinical characteristics and hormonal profiles are shown in Table 1. The demographic data, such as the age at the start of treatment, age of onset, auxological data, BA, and PAH, were found to be comparable in both groups, with no significant differences. Patients are given GnRH agonist medication until their BA reaches roughly 12 years, with the treatment lasting for about 2 years [12].

Following 6 months of treatment, the suppression of LH was evaluated and shown in Table 2. The average LH level was found to be similar in the group receiving 3-month leuprolide acetate and triptorelin pamoate therapy (1.85± 0.73 and 2.08±1.27, P=0.45). In addition, the rate of LH suppression was comparable between the group receiving treatment every 3 months, with rates of 100% and 84.62% (P=0.07) respectively. In the group that received 3-month leuprolide acetate and triptorelin pamoate therapy, the estradiol level was comparable (7.05±4.25 and 6.34±3.00, P=0.55).

The growth parameters measured at the end of the therapy are presented in Table 3. The difference in BA advancement, measured by subtracting CA from BA (2.22±1.09 and 1.76±1.30, P=0.08), and the ratio of BA to CA (1.27±0.14 and 1.21±0.16, P=0.11), did not achieve statistical significance. When comparing the levels of PAH at the ending of treatment to the levels at the start of treatment, both groups showed an increase in PAH at the end of treatment in comparison to the start of treatment in Fig. 1. There was no statistically significant difference in the PAH at the conclusion of treatment compared to the commencement of treatment in the group that received treatment every 3 months (4.19±4.58 and 5.01±2.79, P=0.54).

The most frequently utilized treatment for CPP was the 1-month (4 weeks) depot GnRH analogues until that time. Over the past 7 years, a depot that is available for 3 months has been established. The administration of 2 types of GnRH agonists every 3 months to treat CPP in girls in Thailand has been authorized since 2019. Nevertheless, there is a lack of research that directly compare the effectiveness of these therapy regimens [13,14]. At first, our evaluation primarily focused on assessing their efficacy by analyzing the reduction of LH levels after 6 months of treatment. Criteria for the biochemical efficacy of adequate LH suppression during GnRH analogue therapy are subject to debate. To assess the HPG axis, serum LH or sex steroid can be measured either unstimulated or stimulated (following GnRH analogue administration). The cutoff value for therapeutic monitoring of LH suppression has been investigated using GnRH analogue-stimulated LH levels; however, the appropriate value remains a topic of debate. Based on the International Consortium, the cutoff value for LH suppression in this study was an LH level below 4 IU/L [15]. The results of our study showed that both medications had similar effects in reducing stimulated LH levels in the group receiving treatment every 3 months. The mean LH levels in both groups remained below 4, and there was no noticeable difference in the amount of suppression between the 2 groups. The results align with prior research, which demonstrated LH suppression rates of approximately 84%–100% in both 3 monthly group [16-23]. The present results were also consistent with those from previous studies conducted in predominantly Caucasian populations. In a meta-analysis of earlier trials, it is evident that there are no significant different in outcomes between Caucasian and Asian patients.

Previous research evaluating growth outcomes after 1 year of treatment has not revealed any statistically significant differences in height, the rate at which height increases, or the degree that BA advances between the GnRH agonist preparations [22,24,25]. However, there is a lack of information regarding the assessment of medical effectiveness by analyzing growth characteristics after completing the treatment. The objective of our study was to provide further understanding of the long-term growth effects. Our observation revealed that there was no statistically significant difference in the actual height between individuals who were administered 3-month leuprolide acetate and those who were administered 3month triptorelin pamoate. The results of the present study are consistent with prior research conducted in Italy [13], which showed no significant distinction between 1-month injections of leuprolide acetate and 1-month injections of triptorelin acetate in terms of height, height velocity, and the degree of BA advancement within each group. Similarly, the degree of BA progression in both groups (3-month leuprolide acetate and triptorelin pamoate) was comparable in our study, as measured by the difference between BA and CA and the ratio of BA to CA. Both groups experienced a decrease in BA advancement, with no obvious distinction between the 2 groups. This suggests that both treatments were clinically effective.

When the PAH at the end of treatment was compared to its value at the start of treatment, all patients in our analysis experienced an increase in PAH subsequent to receiving treatment with both GnRH agonist. There was not a significant difference between the 2 GnRH agonist treatments with regard to the restoration of growth potential. Furthermore, absolute changes in BA, weight, height, and PAH at the conclusion of treatment did not reveal any significant differences between the 2 groups of patients.

Our study's limitations include its retrospective design, which results in some missing data, and differences in the quantity of data points for particular parameters, making it challenging to compare the 2 groups. Additionally, some participants in this study use basal LH >0.3 IU/L in the diagnosis of CPP, which is not always indicative of 100% specificity. It is important to emphasize that we did not evaluate the precise final adult height because of the reason that the 3-month group started treatment in 2019, and as of now, none of the patients in this group have attained their final adult height. Despite these limitations, our study provides valuable insights into the comparative effectiveness of the two 3-month GnRH agonist regimens in the treatment of CPP.

In conclusion, both 3-month leuprolide acetate and 3-month triptorelin pamoate treatment regimens demonstrate comparable effectiveness in LH levels and preventing the progression of BA in girl patients undergoing treatment for CPP. PAH is improved in response to both treatment protocols, and there are no significant disparities in PAH observed between the 2 regimens. To validate our findings and assess the ultimate height attained, additional longitudinal research is required.