Dynamic Profiles of Serum Kisspeptin and DLK1 During GnRH Stimulation in Central Precocious Puberty and Premature Thelarche.
BACKGROUND The neuropeptides kisspeptin and Delta-like 1 homolog (DLK1) regulate pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal (HPG) axis, respectively. Given these opposing regulatory roles, quantifying serum kisspeptin and DLK1 levels during gonadotropin-releasing hormone (GnRH) stimulation may serve as novel biomarkers for distinguishing between central precocious puberty (CPP) and premature thelarche (PT) in girls. METHODS A cross-sectional study was conducted on girls presenting with breast development before eight years of age. Participants were stratified into CPP or PT cohorts based on peak luteinizing hormone (LH) levels following GnRH stimulation (CPP: peak LH ≥ 7 IU/L; PT: peak LH < 7 IU/L). Serum samples were analyzed for kisspeptin and DLK1 at baseline, as well as at 60- and 120-minute post-stimulation. RESULTS The study included 40 girls (20 CPP, 20 PT) with comparable baseline characteristics, except for significantly advanced bone age in the CPP group (P < 0.05). Although baseline serum kisspeptin and DLK1 levels showed no significant intergroup differences, their dynamic responses to GnRH stimulation were distinct. At 60 minutes post-stimulation, the percentage change in serum kisspeptin was significantly lower in the CPP group compared to the PT group (median -35.74% vs. 17.66%; P=0.042). Conversely, the percentage change in DLK1 was significantly elevated in CPP patients (78.38% vs. 19.22%; P<0.001). At 120 minutes, the difference in DLK1 percentage change remained significant (P<0.001), whereas kisspeptin levels showed no significant difference (P=0.499). A positive correlation was observed between kisspeptin and DLK1 levels at both baseline and 60 minutes. CONCLUSION Our findings indicate that the dynamic profiles of kisspeptin and DLK1 reflect distinct neuroendocrine mechanisms distinguishing CPP from PT. These findings underscore the complexity of neuroendocrine regulation of puberty involving kisspeptin and DLK1; however, given the considerable overlap between CPP and PT patients observed in this study, their diagnostic potential as standalone or adjunctive clinical tools remains uncertain and would require validation in larger, independent cohorts.