Lipedema most often begins or worsens 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
There are several proposed mechanisms including theories on estrogen receptor imbalance, intracrine estrogen excess, and CAV1 dysfunction.
Estrogen Receptors
Lipedema adipose tissue is subcutaneous fat which exhibits a shift toward estrogen receptor β (ERβ) predominance over ERα.[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 subcutaneous fat can promote 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 the aromatase enzyme which is more prevalent in the buttocks and thighs, increases with age, adiposity, and inflammation. Elevated levels of CYP19A1 expression, which is the gene that codes for aromatase, were found to be higher in lipedema tissue in a study by Bauer et al, yet this is an area we do not yet fully understand. Similarly, we don’t yet have good data on local estrogen metabolism including levels of forms of estrogen like estradiol and estrone, or expression of 17β-HSD1, 17β-HSD2, or 17β-HSD7 that metabolize estrogens. The suspected increased intracrine excess would however create a self-perpetuating cycle of inflammation, fibrosis, and immune dysregulation that we see in lipedema.[2]
Another leading 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] as well as increased systemic insulin resistance and inflammation.
There are also interesting connections between fluctuating estrogen levels and histamine which you can read more about here.
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
- Katzer K, Hill JL, McIver KB, Foster MT. Lipedema and the potential role of estrogen in excessive adipose tissue accumulation. Int J Mol Sci. 2021;22(21):11720.
- Pinto da Costa Viana D, Caseri Câmara L, Borges Palau R. Menopause as a critical turning point in lipedema: the estrogen receptor imbalance, intracrine estrogen, and adipose tissue dysfunction model. Int J Mol Sci. 2025;26(3):1124.
- Kruglikov IL, Joffin N, Scherer PE. The MMP14-caveolin axis and its potential relevance for lipoedema. Nat Rev Endocrinol. 2020;16(4):199-205.
- Rabiee A. Lipedema and adipose tissue: current understanding, controversies, and future directions. Front Cell Dev Biol. 2025;13:1354321.
- Ernst AM, Steiner M, Kainz V, et al. Lipedema: the use of cultured adipocytes for identification of diagnostic markers. Plast Reconstr Surg. 2023;151(6):1227-1236.
- Kruppa P, Gohlke S, Łapiński K, et al. Lipedema stage affects adipocyte hypertrophy, subcutaneous adipose tissue inflammation and interstitial fibrosis. Front Immunol. 2023;14:1182283.
- Wolf S, Rannikko JH, Virtakoivu R, et al. A distinct M2 macrophage infiltrate and transcriptomic profile decisively influence adipocyte differentiation in lipedema. Front Immunol. 2023;14:1158978.
