Periodontal disease and endocrine imbalance: a molecular pathways perspective

Periodontitis is a chronic multifactorial inflammatory disease whose pathological consequences extend well beyond the oral cavity to affect systemic health through the dissemination of pro-inflammatory mediators, bacteremic episodes, and the amplification of low-grade systemic inflammation. Concurrently, the endocrine system functions as a central regulator of periodontal tissue homeostasis, with hormone receptors for estrogens, androgens, glucocorticoids, insulin, thyroid hormones, and vitamin D expressed across the principal cell populations of the periodontium, including gingival fibroblasts, PDL cells, osteoblasts, osteoclasts, and epithelial cells. This narrative review synthesizes current evidence on the molecular pathways mediating the bidirectional relationship between periodontal disease and endocrine imbalance, integrating experimental, clinical, and systems-level bioinformatics data to provide a comprehensive mechanistic framework for this interaction. We examine how estrogen deficiency, progesterone excess, androgen dysregulation, insulin resistance, adipokine imbalance, thyroid dysfunction, glucocorticoid excess or deficiency, and perturbations of the parathyroid hormone and vitamin D axes each contribute to periodontal susceptibility through distinct but convergent molecular mechanisms involving NF- $\kappa$ B activation, NLRP3 inflammasome-driven IL-1 $\beta$ and IL-18 maturation, cytokine network dysregulation, oxidative stress amplification, and disruption of the RANKL/OPG balance governing alveolar bone homeostasis. We also discuss key hub genes including TNF, IL6, LEP, NOS3, STAT3, and VEGFA as molecular nodes that simultaneously participate in endocrine and periodontal signaling, and we highlight the PI3K/Akt, AGE-RAGE, JAK-STAT, Th17 differentiation, and HIF-1 pathways as the most significantly enriched molecular routes of endocrine-periodontal crosstalk. The RANKL/OPG axis emerges as a central integrator of hormonal and inflammatory inputs to alveolar bone metabolism, with estrogen, PTH, glucocorticoids, vitamin D, leptin, and adiponectin each converging on this molecular switch through receptor-mediated mechanisms that are additive to the inflammatory RANKL upregulation driven by IL-1 $\beta$ , IL-6, IL-17, and TNF- $\alpha$ in active periodontal lesions. Emerging pharmacological agents at the endocrine-periodontal interface, including GLP-1 receptor agonists, denosumab, statins, vitamin D supplementation, and specialized pro-resolving mediators, offer mechanistically grounded opportunities for integrated therapeutic strategies that address both oral and systemic disease simultaneously. The diagnostic and therapeutic implications of these molecular relationships demand a fundamental reorientation of clinical management toward interdisciplinary models in which periodontal assessment is incorporated into the evaluation of patients with endocrine disorders, endocrine status is systematically characterized in patients with severe or treatment-refractory periodontitis, and therapeutic decisions in both specialties are made with explicit awareness of the shared molecular architecture linking them.