Central precocious puberty (CPP) is defined as the development of sexual characteristics before 9 years of age in boys and 8 years of age in girls due to activation of the hypothalamic-pituitary-gonadal axis (1, 2). CPP is a rare disease, with an estimated incidence of 1:10,000, but predominantly occurs in girls in more than 95% of cases (3, 4). There are many theories regarding the etiology of idiopathic CPP. One of which points out that these girls have a higher percentage of body fat for their chronological age, where leptin has a main role (5). Leptin acts through its receptor to stimulate the secretion of kisspeptin, a hypothalamic hormone, which in turn promotes the secretion of GnRH in the arcuate nucleus (6, 7).

It is common for girls with CPP to be overweight or obese at the time of diagnosis, but there are conflicting results as to whether weight is increased during or after receiving treatment with GnRH analogs (GnRHa), because there are studies indicating that the BMI increases and in others that it decreases (8–13). However, CPP is considered to be a risk factor for the development of cardiometabolic disorders in adult life, regardless of the presence of obesity (14, 15).

Adipose tissue is considered an endocrine organ that produces a wide variety of biologically active adipokines, such as leptin, adiponectin, tumor necrosis factor-α and interleukin-6 (16).

These adipokines plays a pathophysiological link between dysfunctional adipose tissue and cardiometabolic factors (17). Leptin is produced proportionally to the amount of body fat, and in patients with obesity there is an association of high leptin levels with cardiometabolic factors and metabolic syndrome (18, 19), while high levels of adiponectin are associated with a better metabolic profile in these patients (20). However, it has been observed that the leptin/adiponectin ratio (LAR) identify dysfunctional adipose tissue more accurately (21, 22). Thus, higher LAR values have been considered a better marker of insulin resistance and metabolic syndrome than serum leptin or adiponectin levels (23). Although the possible role of LAR in girls with CPP has not been studied, it is hypothesized that higher LAR values are a better predictor of weight gain than high leptin levels or low adiponectin levels.

The aim of this study was to determine if the leptin, adiponectin levels, and LAR can predict weight gain at the end of GnRha treatment in girls with CPP.

Different studies have shown that girls with CPP have a higher risk of weight gain during treatment with GnRHa, as well as having a more adverse cardiometabolic profile, but information on possible associated factors is lacking. To our knowledge, this is the first study to identify LAR as a prognostic marker associated with increased in weight gain in patients with CPP.

Our findings may be relevant, since there is controversy about whether the greater adiposity that CPP patients have at diagnosis may be the main factor related to in the increased cardiovascular risk. In general, these patients tend to increase zBMI, but when analyzed according to their baseline nutritional status, it has been found that CPP girls with normal weight at diagnosis, their zBMI increases more than when they are classified as overweight/obese (8, 9). Park J et al. included 59 patients, of whom 35.6% were overweight or obese; during follow-up until final height was reached, no change in zBMI was observed, but in patients who started overweight/obese, there was a decrease in zBMI (p<0.05) (13). Similarly, in this study, the increase in zBMI was statistically significant in the 38 patients with BMI < 94^th ( Figure 1B ), and almost all of those with BMI >95^th remained in the same zBMI.

Adipose tissue is metabolically active and secretes adipokines, such as leptin and adiponectin; the former causes vascular inflammation and insulin resistance, while the latter inhibits adherence molecules and increases the production of anti-inflammatory cytokines, such as IL-10 (32–34). In addition, leptin has been shown to be useful prognostic factor in weight gain and in the development of type 2 diabetes mellitus (35, 36). LAR represents a marker of the pathophysiological function of both adipokines and may indicate an imbalance in proinflammatory and anti-inflammatory conditions, as well as adipose tissue dysfunction (37). Under normal conditions, the ratio of leptin and adiponectin is 1:2, which means LAR values of 0.5; thus, higher values have been associated with an increase in cardiovascular risk (21).

To verify the relationship between leptin and adiponectin, studies have been carried out in human white preadipocytes. Singh et al. reported that leptin may regulate adiponectin mRNA via extracellular signal-regulated kinase (ERK)-dependent activation of signal transducer and activator of transcription 3 (STAT3), but in obese people these pathways are altered (38).

Adipose tissue dysfunction has been regarded as a form of oxidative stress, in which thiobarbituric acid reactive sub-stances (TBARS) are increased, as well as C-reactive protein (CRP), serum amyloid A (SAA) and osteopontin (OPN) levels (39–42). In adult patients with metabolic syndrome, a positive correlation of LAR levels with CRP has been described, suggesting that adipose tissue dysfunction is related to elevated LAR values (23). This information is consistent with findings from more recent studies in which LAR values could be a more efficient predictor of obesity-related complications compared to leptin or adiponectin levels (41, 43, 44).

LAR values have also been evaluated in children. Some studies in patients without comorbidities with 6-years of follow-up have reported that high leptin levels and LAR are predictors in nonobese subjects. However, it is controversial which of the two is a better predictor; Zhang et al, identified leptin as being better than LAR in change of zBMI (leptin β=0.209 and LAR β=0.146), while Li et al, observed that LAR was better than leptin in change of body fat percentage (leptin β=0.310 and LAR β=0.420) (45, 46). Among girls with CCP we also found that leptin levels and LAR are associated with increased in weight gain, but LAR seems a better marker ( Tables 2 , 3 ). In contrast, Yoo JM et al. reported that neither leptin, adiponectin, nor LAR were predictors of weight gain girls with CPP (47); this difference could be due to a shorter follow-up time, or because the analysis was not limited to patients with greater weight gain, as in the present study.

Therefore, we consider that, at the diagnosis of CPP, leptin levels and LAR can be used as a prognostic marker to identify those girls who are at greater risk of significantly increasing their weight during treatment with GnRHa. This would help to offer early interventions to reduce the probability of developing comorbidities related to obesity in adulthood, such as metabolic syndrome, polycystic ovarian syndrome, and type 2 diabetes (48, 49).

As for the limitations of the study, we should mention that the sample size was small, so it seems necessary to carry out more studies to verify our findings. Likewise, in other studies, an attempt should be made to establish the LAR cut-off point that identifies patients with a higher risk of increasing their zBMI.

In patients with CPP, higher leptin levels and LAR values appear to be associated with significantly greater weight gain during GhRHa treatment, particularly in girls starting with BMI < 94 percentile.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the research protocol by the Hospital de Pediatria National Medical Center XXI Century, Instituto Mexicano del Seguro Social ethics and research committee. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Conceptualization, methodology & formal analysis: MV-K & JZ-C. Investigation: JZ-C, LM-A, LD-S, EG-M, AR-H. Writing, review & editing: MV-K & JZ-C. All authors contributed to the article and approved the submitted version.