Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model
Abstract
1. Introduction
2. Results
3. Discussion
3.1. The Role of Estradiol and Its Receptors
3.2. Intracrine Production of Estradiol in Adipose Tissue
3.3. Progesterone Resistance
3.4. How Menopause Affects Lipedema
3.5. Therapeutic Implications
4. Material and Methods
- Estrogen receptor signaling (ERα, ERβ) in adipose tissue;
- Intracrine estrogen metabolism via aromatase, 17β-HSD1, and 17β-HSD2 enzymes;
- The role of menopause-induced estrogen deficiency in adipose tissue dysfunction;
- The immunometabolic consequences of receptor imbalance, including inflammation and fibrosis;
- Parallels between lipedema and other estrogen-driven gynecological disorders.
5. Conclusions
Funding
Conflicts of Interest
Abbreviations
ERα | Estrogen Receptor Alpha |
ERβ | Estrogen Receptor Beta |
PRβ | Progesterone Receptor Beta |
17β-HSD1 | 17β-Hydroxysteroid Dehydrogenase Type 1 |
17β-HSD2 | 17β-Hydroxysteroid Dehydrogenase Type 2 |
HRT | Hormone Replacement Therapy |
FSH | Follicle-Stimulating Hormone |
LH | Luteinizing Hormone |
GLP-1 | Glucagon-Like Peptide-1 |
GIP | Glucose-Dependent Insulinotropic Polypeptide |
LPL | Lipoprotein Lipase |
GLUT4 | Glucose Transporter Type 4 |
VEGF | Vascular Endothelial Growth Factor |
IL-6/IL-1β/IL-18 | Interleukin-6/Interleukin-1 beta/Interleukin-18 |
TNF-α | Tumor Necrosis Factor Alpha |
HIF-1α | Hypoxia-Inducible Factor 1 Alpha |
NF-κB | Nuclear Factor Kappa B |
JNK | c-Jun N-terminal Kinase |
UCP1 | Uncoupling Protein 1 |
RAAS | Renin–Angiotensin–Aldosterone System |
STRAW | Stages of Reproductive Aging Workshop |
SWAN | Study of Women’s Health Across the Nation |
MASH | Metabolic Associated Steatohepatitis |
CD163+ | Cluster of Differentiation 163 Positive (M2 macrophage marker) |
MCP-1 | Monocyte Chemoattractant Protein-1 |
ERK | Extracellular Signal-Regulated Kinase |
DNA | Deoxyribonucleic Acid |
E2 | Estradiol |
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Pathophysiological Change | Author and Year | Summary of Findings |
---|---|---|
Estrogen Receptors (ERα and ERβ) | Simpson et al., 1989 [8] | The climacteric period decreases ERα expression and compensatorily increases ERβ in adipose tissue. |
Foryst-Ludwig and Kintscher, 2010 [13] | Estrogen deficiency in menopause and lipedema reduces ERα and increases ERβ, promoting inflammation, fibrosis, and insulin resistance. | |
Katzer K et al., 2021 [4] | Dysregulation of estrogen receptors (ERα/ERβ) and local estrogen production in adipose tissue may lead to excessive fat accumulation, particularly in the lower body, a hallmark of lipedema. | |
Aromatase (CYP19A1) | Simpson et al., 1989 [8] | Subcutaneous adipose tissue synthesizes estrogens via aromatase and 17β-HSD. |
Szél et al., 2014 [16] | Lipedema exhibits increased aromatase activity and enzymatic dysregulation. | |
17β-HSD 1 and 2 | Zeitoun et al., 1998 [19] | In conditions like endometriosis, 17β-HSD2 deficiency prevents the conversion of estradiol into estrone. |
Szél et al., 2014 [16] | There is an increase in 17β-HSD1, which converts estrone into active estradiol, intensifying local estrogenic activation. | |
Bardhi et al., 2024 [20] | 17β-HSDs in adipose tissue convert weak steroids like estrone into potent forms such as estradiol, underscoring the role of local hormone metabolism in adipose function. | |
Al-Ghadban et al., 2024 [21] | Estrogen enhances HSD17B7 and LIPE expression in lipedema cells, supporting a direct role of estrogen metabolism in disease pathogenesis. | |
Viana and Câmara, 2025 [22] | Progesterone resistance reduces 17β-HSD2 activity, impairing estradiol inactivation. | |
Progesterone Resistance | O’Brien et al., 1998 [18] | Subcutaneous adipose tissue expresses progesterone receptors, suggesting an active local hormonal role. |
Viana and Câmara, 2025 [15] | The failure of progesterone to modulate adipose tissue allows intracrine estradiol to sustain the inflammatory state. | |
Mitochondrial Dysfunction | Geraci et al., 2021 [23] Renke et al., 2023 [24] | Mitochondrial dysfunction induced by estrogen deficiency reduces basal metabolism, contributing to sarcopenia and insulin resistance. |
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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, 7074. https://doi.org/10.3390/ijms26157074
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. International Journal of Molecular Sciences. 2025; 26(15):7074. https://doi.org/10.3390/ijms26157074
Chicago/Turabian StylePinto da Costa Viana, Diogo, Lucas Caseri Câmara, and Robinson Borges Palau. 2025. "Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model" International Journal of Molecular Sciences 26, no. 15: 7074. https://doi.org/10.3390/ijms26157074
APA StylePinto da Costa Viana, D., Caseri Câmara, L., & Borges Palau, R. (2025). Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model. International Journal of Molecular Sciences, 26(15), 7074. https://doi.org/10.3390/ijms26157074