Lipedema most often begins during a period of significant hormonal change such as puberty, pregnancy, or menopause and almost exclusively effects women. Hormonal changes trigger lipedema primarily through estrogen-mediated mechanisms that disrupt normal adipose tissue metabolism. [1]
A Focus on Estrogen
The proposed pathophysiology centers on estrogen receptor imbalance and altered local estrogen metabolism. Lipedema adipose tissue exhibits a shift toward estrogen receptor β (ERβ) predominance over ERα, which disrupts normal metabolic signaling.[2] ERα and ERβ exert opposing biological effects in many tissues with ERα being the principal mediator of estrogen’s anti-obesity effects, down regulating adipogenesis and lipogenesis (fat cell and fat production) and protecting against adipose tissue inflammation and fibrosis. Collectively, the shift towards ERβ seen in lipedema promotes the formation of new fat cells (adipogenesis) and lipid deposition and removes the ERα protection from inflammation and fibrosis.
A local elevation in estradiol (estrogen) is sustained by an upregulation of enzymes, particularly aromatase and 17β-HSD1 and suppression of 17β-HSD2. This creates a self-perpetuating cycle of inflammation, fibrosis, and immune dysregulation.[2]
An alternative proposed mechanism involves caveolin 1 (CAV1) dysfunction. Caveolins are proteins found in “little caves” or caveolae in cell membranes, including fat cells. They are involved in things like cell signaling, transporting things across cells, and more. Reduced CAV1 activity may lead to uncoupling of feedback mechanisms between CAV1, matrix metalloproteinase MMP14, and estrogen receptors, resulting in ERα activation and impaired lymphatic regulation.[3] This could explain the adipose hypertrophy (enlargement of fat cells), vascular and lymphatic dysfunction, and estrogen dependence characteristic of lipedema.[3]
Menopause appears to be a critical juncture in disease progression, as declining systemic estrogen paradoxically amplifies adipose tissue dysfunction through suppressed ERα signaling and enhanced ERβ activity.[2][4]
Gene Expression and Epigenetics
Gene expression studies show upregulated adipogenic (fat-promoting) genes in lipedema fat cells and altered inflammatory profiles associated with macrophages. These genes could theoretically be “turned on” from epigenetic regulation during these hormonal shifts, however there are currently no studies that have specifically explored epigenetic mechanisms in lipedema. [5-7]
The influence of hormones on lipedema onset and progression gives rise to many clinical questions. Could hormone targeted therapies be beneficial in lipedema? What is the influence of oral contraceptives on lipedema? Is HRT helpful or harmful for lipedema?
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Sources
- Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation. International Journal of Molecular Sciences. 2021. Katzer K, Hill JL, McIver KB, Foster MT.
- Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model. International Journal of Molecular Sciences. 2025. Pinto da Costa Viana D, Caseri Câmara L, Borges Palau R.
- The MMP14-caveolin Axis and Its Potential Relevance for Lipoedema. Nature Reviews. Endocrinology. 2020. Kruglikov IL, Joffin N, Scherer PE.
- Lipedema and Adipose Tissue: Current Understanding, Controversies, and Future Directions. Frontiers in Cell and Developmental Biology. 2025. Rabiee A.
- Lipedema: The Use of Cultured Adipocytes for Identification of Diagnostic Markers. Plastic and Reconstructive Surgery. 2023. Ernst AM, Steiner M, Kainz V, et al.
- Lipedema Stage Affects Adipocyte Hypertrophy, Subcutaneous Adipose Tissue Inflammation and Interstitial Fibrosis. Frontiers in Immunology. 2023. Kruppa P, Gohlke S, Łapiński K, et al.
- A Distinct M2 Macrophage Infiltrate and Transcriptomic Profile Decisively Influence Adipocyte Differentiation in Lipedema. Frontiers in Immunology. 2023. Wolf S, Rannikko JH, Virtakoivu R, et al.
