{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:54:58Z","timestamp":1790668498495,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lipedema is a chronic, estrogen-sensitive adipose tissue disorder characterized by disproportionate subcutaneous fat accumulation, fibrosis, inflammation, and resistance to fat mobilization. Despite its high prevalence, lipedema remains poorly understood and frequently misdiagnosed. This narrative review proposes a novel pathophysiological model in which menopause acts as a critical turning point in the progression of lipedema, driven by estrogen receptor imbalance (ER\u03b2 predominance over ER\u03b1), intracrine estrogen excess, and adipose tissue dysfunction. We demonstrate how menopause amplifies adipose tissue dysfunction by suppressing ER\u03b1 signaling; enhancing ER\u03b2 activity; and disrupting mitochondrial function, insulin sensitivity, and lipid oxidation. Concurrently, the upregulation of aromatase and 17\u03b2-HSD1, combined with the suppression of 17\u03b2-HSD2, sustains localized estradiol excess, perpetuating inflammation, fibrosis, and immune dysregulation. The molecular signature observed in lipedema closely mirrors that of other estrogen-driven gynecological disorders, such as endometriosis, adenomyosis, and uterine fibroids. Understanding these molecular mechanisms highlights the pivotal role of menopause as a catalyst for disease progression and provides a rationale for targeted therapeutic strategies, including hormonal modulation and metabolic interventions. This review reframes lipedema as an estrogen receptor-driven gynecological disorder, offering a new perspective to improve clinical recognition, diagnosis, and management of this neglected condition.<\/jats:p>","DOI":"10.3390\/ijms26157074","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T08:02:06Z","timestamp":1753257726000},"page":"7074","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9245-2509","authenticated-orcid":false,"given":"Diogo","family":"Pinto da Costa Viana","sequence":"first","affiliation":[{"name":"Brazilian Society of Endocrinology and Metabolism in Sports and Exercise, Florian\u00f3polis 88070-800, Brazil"},{"name":"Brazilian Society of Obesity Medicine, Florian\u00f3polis 88070-800, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Caseri C\u00e2mara","sequence":"additional","affiliation":[{"name":"Brazilian Society of Obesity Medicine, Florian\u00f3polis 88070-800, Brazil"},{"name":"Department of Specialization in Clinical Anabolism College of Governance, Engineering, and Education of S\u00e3o Paulo-FGE-SP, S\u00e3o Paulo 18705-770, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robinson","family":"Borges Palau","sequence":"additional","affiliation":[{"name":"Brazilian Society of Obesity Medicine, Florian\u00f3polis 88070-800, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.7326\/0003-4819-34-5-1243","article-title":"Lipedema of the legs; A syndrome characterized by fat legs and edema","volume":"34","author":"Wold","year":"1951","journal-title":"Ann. 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