Lipedema is a chronic adipose tissue disorder characterized by disproportionate and often painful enlargement of the extremities, occurring predominantly in women. Despite increasing clinical recognition, the underlying pathophysiology remains incompletely understood and is likely multifactorial. Existing evidence suggests contributions from vascular alterations, adipose tissue remodeling, inflammatory activation, hormonal influences, and lymphatic dysfunction. This review proposes a hypothesis-generating integrative framework in which lipedema may reflect a regenerative imbalance of subcutaneous adipose tissue. Within this model, genetically and hormonally modulated endothelial permeability could promote activation of perivascular adipose-derived stromal/stem-cell niches and stromal vascular fraction signaling pathways, thereby facilitating coupled angiogenesis and adipogenesis. Progressive adipocyte hyperplasia and hypertrophy may subsequently contribute to inflammatory remodeling, pain generation, and secondary impairment of dermal and subdermal lymphatic drainage. The proposed framework attempts to integrate clinical, histological, imaging, molecular, and endocrine observations into a biologically coherent conceptual model. At the same time, the review emphasizes the current limitations of the available evidence, the heterogeneity of lipedema phenotypes, and the ongoing controversies regarding disease progression, obesity overlap, and the relative role of lymphatic dysfunction. Finally, the potential mechanistic rationale of lymphatic-sparing liposuction is discussed in the context of tissue decompression, restoration of lymphatic transport, and interruption of persistent adipose remodeling. The model presented here should be interpreted as a hypothesis-generating conceptual scaffold requiring prospective validation. Importantly, the present framework should be interpreted as a biologically plausible and hypothesis-generating conceptual model rather than a definitive mechanistic doctrine. Several proposed interactions remain associative and require prospective biological validation.

Lipedema is a painful, chronic and progressive disorder of subcutaneous adipose tissue characterized by disproportionate, symmetrical fat accumulation in the extremities—typically the legs and less often the arms—while sparing hands and feet. It is clinically distinct from obesity and lymphoedema, affects almost exclusively women, and often exacerbates during hormonal transition phases. This paper proposes a unifying pathophysiological concept in which lipedema reflects a regenerative imbalance of adipose tissue. A genetically and estrogen-modulated increase in endothelial permeability (“leaky vessels”) is suggested to activate perivascular/mural adipose-derived stem cells (ADSCs), thereby initiating coupled angiogenesis and adipogenesis. The stromal vascular fraction (SVF) is described as a central mediator, with SVF-derived extracellular vesicles and characteristic microRNAs promoting adipocyte hyperplasia and hypertrophy and leading to large, metabolically less active adipocytes. The organism attempts to counterbalance this surplus through inflammatory activation of mast cells and macrophages; however, inefficient clearance of excess adipocytes (including “crown-like” structures) sustains inflammation and pain. Progressive adipose expansion may compress lymphatic capillaries and precollectors, resulting in dermal and subdermal lymphatic congestion and contributing to oedema and symptom progression. Increased aromatase activity and local estrogen availability are discussed as additional amplifiers of adipogenesis and inflammatory remodeling. Finally, lymphatic-sparing liposuction is outlined as a mechanistically plausible intervention that can reduce tissue pressure, improve lymphatic drainage, and alleviate key symptoms.