Genetic Polymorphisms and Vascular Dysfunction in Lipedema: Implications for a Non-Hormonal Pathophysiological Model

Lipedema is a chronic, progressive adipose tissue disorder predominantly affecting women and has been widely proposed as an estrogen-dependent condition despite the lack of objective causal evidence. In contrast, increasing data implicate genetic heterogeneity, endothelial dysfunction, and altered vascular permeability as central features of the disease. This review critically reassesses the estrogen-dependence hypothesis in light of emerging genetic and vascular evidence. These findings highlight molecular pathways linking endothelial dysfunction and adipose tissue dysregulation as central features of the disease. Methods: A narrative literature review was conducted using PubMed, Cochrane Library, and Google Scholar databases. Searches combined the terms “lipedema,” “lipoedema,” “estrogen,” “hormonal dependence,” “genetic polymorphism,” “endothelial dysfunction,” “vascular permeability,” “microangiopathy,” and “adipose tissue,”. Original research articles, reviews, consensus statements, and experimental studies were included. Given the narrative design, no formal inclusion criteria, quality assessment, or meta-analytic procedures were applied. Results: Across multiple cohorts, no studies demonstrated that estrogen levels, estrogen receptor expression, aromatase activity, or estrogen-related signaling pathways act as primary causal triggers of lipedema. Conversely, consistent genetic, transcriptomic, and histopathological findings reveal marked genetic heterogeneity, dysregulated adipose tissue proliferation, extracellular matrix remodeling, microangiopathy, and increased endothelial permeability. Variants affecting adipogenesis, connective tissue integrity, vascular function, and lymphatic regulation have been repeatedly identified, alongside early endothelial structural and functional abnormalities. Conclusion: Current evidence does not consistently support classifying lipedema as an estrogen-dependent disease. While estrogen may modulate inflammatory and metabolic processes relevant to disease expression, its role appears secondary rather than causative. Genetic predisposition and vascular dysfunction emerge as more consistent contributors to lipedema pathophysiology, supporting integrative, mechanism-based models to guide future research and clinical approaches.