Syndrome differentiation and treatment of pediatric central precocious puberty: role of the spleen-kidney axis

Vollständiger Abstract

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Pediatric central precocious puberty (CPP) is driven by premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, along with immune-inflammatory imbalance, metabolic dysfunction, obesity, and gut microbiota-derived signals. According to traditional Chinese medicine (TCM) principles, kidney yin deficiency with hyperactive ministerial fire and spleen deficiency with phlegm-dampness form the basis for central pubertal activation and peripheral metabolic-inflammatory burden, thus supporting a combined approach for obesity-related or mixed-pattern CPP. Representative prescriptions include modified Zhibai Dihuang pills with Liujunzi decoction and modified Danzhi Xiaoyao powder with Erchen decoction, which integrate kidney yin-nourishment and ministerial fire-clearance with spleen qi-strengthening and phlegm resolution. Available clinical evidence suggests potential benefits in controlling secondary sexual characteristics, reducing gonadotropin and sex-steroid levels, and slowing bone-age advancement. Mechanistic studies indicate possible regulation of kisspeptin/GPR54/GnRH and LH/FSH-sex-steroid signaling, Th1/Th2/Treg homeostasis, NF-κB/NLRP3 pathways, adipokine imbalance, insulin resistance, hypothalamic inflammation, and gut microbiota-associated metabolism. However, most mechanistic links remain indirect, comparative trials are scarce, and direct correction of pathogenic MKRN3 or DLK1 variants has not been demonstrated. In this review, we have discussed the role of kidney and spleen dysfunction in CPP and explored the underlying mechanisms – particularly in the context of the neuro-endocrine-immune network that links central neuroendocrine activation with peripheral immune-metabolic signals. In addition, the application of TCM in the management of CPP, and the translational challenges of applying TCM as an adjunct to established CPP management have also been explored. Future research should prioritize CPP-specific pathway validation, identification of syndrome biomarkers, multi-omics-based stratification, multicenter trials, and long-term pediatric safety monitoring.