Precocious Puberty in Girls: Pathogenesis, Genetic Architecture and Emerging Molecular Therapies

Precocious puberty, defined as the onset of secondary sexual characteristics before age 8 in girls and 9 in boys, occurs more frequently in females and carries significant medical, psychosocial, and long-term health consequences. This review synthesizes current knowledge on the molecular, genetic, epigenetic, and environmental determinants of early pubertal onset, with a particular focus on female precocious puberty. Central precocious puberty (CPP) arises from premature activation of the hypothalamic–pituitary–gonadal (HPG) axis, driven by dysregulation of kisspeptin–GPR54 signaling, neurokinin B pathways, and inhibitory factors such as MKRN3 and DLK1. Peripheral precocious puberty (PPP), by contrast, results from gonadotropin-independent estrogen production due to somatic mutations (e.g., GNAS1 in McCune- Albright syndrome) or hormone-secreting ovarian tumors. Environmental exposures, particularly endocrine-disrupting chemicals (EDCs), and metabolic factors such as obesity and leptin excess, further contribute by altering neuroendocrine signaling and inducing epigenetic modifications of key puberty-related genes. Current therapeutic standards rely on gonadotropin-releasing hormone (GnRH) agonists to suppress HPG activation, but emerging approaches—including kisspeptin and neurokinin B antagonists, epigenetic modulators, and gene-based strategies—offer promise for precision medicine. By integrating neuroendocrine biology, genetic architecture, and environmental risk factors, this review underscores the complexity of pubertal regulation and highlights future directions for early diagnosis and targeted therapy in precocious puberty.