· Both Leuprolide acetate and Triptorelin pamoate were effective in suppressing luteinizing hormone (LH) levels and improving predicted adult height (PAH) in overweight and obese girls with central precocious puberty (CPP).

· The study found no significant difference in LH suppression and PAH outcomes between the two treatment groups.

· The findings suggest these 2 gonadotropin-releasing hormone agonists offer comparable therapeutic benefits in treating CPP in overweight and obese girls with CPP.

Central precocious puberty (CPP) is characterized by the early activation of the hypothalamic-pituitary-gonadal (HPG) axis in girls who are younger than 8 years old [1]. Girls account for nearly 90% of CPP cases for which the etiology is unknown [2]. The diagnosis of CPP in girls is based on the physical examination findings of early initiation of menstruation, stunted growth caused by the premature fusion of growth plates, and mental and social dysfunction [1]. Obesity is more prevalent in girls with CPP than in those without the condition.

Standard treatments for CPP are the administration of gonadotropin-releasing hormone (GnRH) agonists [3]. These analogs prevent pubertal activation and suppress gonadotropin production by persistently adhering to pituitary GnRH receptors. This process involves the downregulation of GnRH receptors that subsequently leads to the suppression of the HPG axis [4,5]. The essential findings for assessing treatments as successful are deceleration of bone aging, attainment of final adult height that is near the normal range, regression of pubertal development, and reduction of growth velocity [3,6,7].

Currently, a variety of GnRH analog formulations are available for the treatment of CPP. These include leuprolide acetate and triptorelin pamoate, 2 therapeutics that have been demonstrated to effectively suppress the pituitary-gonadal axis and pubertal development. However, data on the relative effectiveness of the different formulations are scarce, particularly data on the relative effectiveness of these therapies in the overweight and obese population of young female CPP patients. A previous study using fixed and weight-based dosages did demonstrate no significant differences in GnRH agonist treatment outcomes [8]; but no data on the relative effectiveness of various GnRH agonist medications, particularly in overweight and obese young girls with CPP, are available. Therefore, the objective of our study was to assess the relative effectiveness of leuprolide acetate and triptorelin pamoate in suppressing luteinizing hormone (LH) levels at 6 months posttreatment and to assess predicted adult height (PAH) at the conclusion of the treatment in overweight and obese girls experiencing CPP.

Data from a cohort of 69 overweight or obese girls who were diagnosed with CPP were analyzed in this study. Of these subjects, 48 were treated with leuprolide acetate; the remaining 21 participants were administered triptorelin pamoate therapy. The initial clinical characteristics of the patients and dosage of the 2 medications are shown in Table 1. The demographic data, including the age at onset; auxological data; bone age; and PAH were compared between the 2 groups. No significant differences between the groups were observed. GnRH agonists are typically administered to patients until a bone age of approximately 12 years is achieved. This process usually requires 2 to 3 years of treatment. In this study, the level of LH suppression was assessed at 6 months posttherapy. The LH suppression results are illustrated in Table 2. The average LH level was comparable in the 2 treatment groups, those that received leuprolide acetate and those that were administered triptorelin pamoate, 2.31±1.34 and 1.95±1.45, respectively, with a P-value=0.46.

Subjects in both groups exhibited an increase in PAH at the conclusion of treatment (Table 3) compared to their PAHs at the initiation of treatment. At the conclusion of treatment, there was no statistically significant difference in the PAH and average bone age (PAH-av) between the 2 groups, 159.06±56.7 and 157.60±7.00 with a P-value of 0.60 (Fig. 1). Compared to baseline BMI SDS measurements, both treatment groups demonstrated substantial increases in BMI SDS at the end of therapy (Table 4).

Previously, depot GnRH agonist administration was the predominant treatment for CPP. However, Thailand has now approved 2 newer GnRH agonists for treatment of girls with CPP. Data on the relative effectiveness of these 2 therapeutics are lacking, though; studies comparing the benefits of these treatment regimens, particularly in overweight and obese girls with CPP, are necessary [1, 13, 14]. One of these therapeutics, leuprolide acetate, is a synthetic nonapeptide analog of GnRH that is more potent than this natural hormone. In triptorelin pamoate, another synthetic GnRH analog, D-tryptophan is substituted for L-glycine at the sixth amino acid position of the natural hormone. This modification to GnRH increases resistance to enzymatic degradation and pituitary receptor affinity for the pituitary receptor. Therefore, the treatment involves increased plasma half-life and effectiveness of this analog compared to GnRH. Triptorelin pamoate is 35 times more effective than leuprolide acetate and has a longer half-life than GnRH, but the comparative effectiveness of the 2 analogs after completion of therapy has never been tested in overweight and obese young girls with CPP. Childhood obesity is a predictor of morbidity and mortality in adulthood [15], and girls with CPP are substantially more likely to be overweight or obese than their counterparts without CPP. The effectiveness of GnRH agonist treatment in suppressing the HPG axis in overweight and obese girls with CPP has been a topic of debate, but this research question has not been tested. In our study, we identified no significant difference between the 2 treatment groups in terms of their dosage per kilogram over a four-week period, approximately 100 μg per kg. This amount is equal to the standard CPP treatment dosage used in Europe.

Initially, we primarily sought to conduct a comparative assessment of treatment effectiveness by documenting the reduction in LH levels after 6 months of treatment. However, the methods for clinical assessment of the biochemical efficacy of LH suppression during GnRH analog therapy are not universally accepted. GnRH-stimulated or -unstimulated serum LH or sex steroidal hormone levels can be measured to evaluate the HPG axis. However, a standard cutoff value for monitoring and adequate therapeutic LH suppression achievement has also not been universally accepted despite undergoing GnRH agonist-stimulated testing. The cutoff value for LH suppression in that International Consortium investigation was an LH level below 4 IU/L [15]. Using this standard, our results indicated that both treatments performed satisfactorily; both treatments resulted in GnRH-stimulated LH suppression test reductions to mean LH levels below 4 IU/L [12]. The findings are consistent with those of previous research conducted on girls diagnosed with CPP. Those results indicated that LH suppression rate was approximately 84%–100% with the use of either of the 2 medications [14,16-21]. Our results also agreed with those of previous studies conducted in predominantly Caucasian populations, and a meta-analysis of previous trials demonstrated that there were no significant differences in outcomes between Caucasian and Asian patients.

In previous assessments of growth parameters after 1 year of treatment, no statistically significant differences in height attainment, the rate at which height increased, or the degree to which bone age advanced were noted between the GnRH agonist preparations in tests on girls with CPP [17,22,23]. Nevertheless, medical effectiveness evaluation information on posttreatment growth characteristics are still lacking, particularly in the population of overweight and obese girls with CPP. Therefore, our research focused on this population. We expanded the scientific knowledge base concerning the long-term growth effects of these treatments in this population of overweight and obese girls diagnosed with CPP. Our testing of the therapies demonstrated that there was no statistically significant difference in the actual height of individuals who were administered leuprolide acetate and those who were administered triptorelin pamoate, and both treatments were clinically effective.

Comparisons of pretreatment and posttreatment PAHs demonstrated that all patients in our analysis experienced an increase in PAH after receiving treatment with either GnRH agonist. The restoration of growth potential was not substantially different between the 2 GnRH agonist regimens. At the conclusion of the treatment, the 2 patient groups did not demonstrate any significant differences in terms of weight, height, or PAH.

Our interpretation of the data is supported by our demonstration that the BMI SDS remained elevated throughout the duration of treatment, indicating that the expected reduction in growth velocity in overweight and obese girls was substantial. These patients exhibited comparable height SDS levels prior to and following GnRH agonist treatment. In conjunction with medical management, healthy lifestyle interventions such as dietary modifications, physical activity, and psychosocial support may offer significant benefits. These interventions may contribute to a slower rate of pubertal progression and improved overall health outcomes.

The retrospective design of our study resulted in occurrence of missing data, and the variable number of data points for specific parameters created difficulties in comparing the 2 treatment groups. Also, significantly, we did not evaluate the precise final adult height because the triptorelin pamoate group patients had not yet attained their final adult height. The initiation of their therapy was delayed until 2019. Despite these limitations, our research results do provide important insights into the comparable effectiveness of the 2 tested GnRH agonist regimens in the treatment of overweight and obese girls experiencing CPP.

In conclusion, the leuprolide acetate and triptorelin pamoate treatment regimens exhibited similar effectiveness in controlling LH levels and preventing the progression of bone age in overweight and obese young female patients who were receiving treatment for CPP. Both treatment protocols resulted in an improvement in PAH, and there were no significant differences in PAH between the 2 treatment groups. Additional longitudinal research is necessary to verify our findings and evaluate the final height achieved by the study subjects.