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Lipedema is a chronic, progressive, and often underdiagnosed disease characterized by the pathological, bilateral, and symmetrical accumulation of adipose tissue. This distribution results in disproportionate and painful swelling of the limbs. Typically extending distally from the hips, this predominantly female condition is frequently misidentified as lifestyle-induced obesity or bilateral lymphedema. This review aims to provide a comprehensive overview of the current understanding of structural and functional abnormalities in myocardial dimensions, mechanics, valves, and major arteries in patients with lipedema. According to the existing literature, left atrial enlargement, left ventricular rotational abnormalities, mitral annular dilation, and increased aortic stiffness have been identified in patients with lipedema. These findings suggest latent but significant alterations in left heart physiology. Although current data remain limited and are primarily focused on the left heart and the aorta, the rapid evolution of cardiac imaging technologies suggests that both clinical knowledge and the body of research in this field are poised for significant expansion.

Lipedema is a chronic disorder characterized by the abnormal and disproportionate accumulation of painful subcutaneous adipose fat, primarily affecting the lower limbs and occurring almost exclusively in women. The aim of this controlled cross-sectional study was to compare body image, psychological distress, and psychological well-being in women with (n = 77) and without lipedema (n = 32). Psychological functioning was assessed using validated measures of depressive symptoms (PHQ-9), eating attitudes (EAT-26), perceived stress (PSS), medically unexplained symptoms (M.U.S.), psychological well-being (WHO-5), life satisfaction (SWLS), psychological flexibility (AAQ-II), pain intensity (VAS), together with measures of body image, lifetime psychological burden, maladaptive cognitive beliefs, symptom severity, and anthropometric parameters. Compared with controls, women with lipedema reported significantly greater body image dissatisfaction, perceived distress, M.U.S., depressive symptoms, disordered eating attitudes, and pain, together with lower psychological well-being, life satisfaction, and psychological flexibility (all p < 0.001). Within the lipedema group, PHQ-9 scores were significantly predicted by M.U.S. scores, maladaptive cognitions, and pain intensity (VAS), whereas EAT-26 scores were predicted by PHQ-9 scores and maladaptive cognitions. These findings indicate that lipedema is associated with a substantial psychological burden and support integrating psychological assessment and intervention into multidisciplinary care.

Lipedema and obesity are often misdiagnosed or clinically confused yet arise via distinct mechanisms, complicating diagnosis and treatment. This review synthesizes evidence differentiating these conditions across genetic, hormonal, inflammatory and mechanical pathways to identify therapeutic targets. Lipedema may involve genetic predisposition (forkhead box C2 [FOXC2], prospero homeobox 1 [PROX1]), hormonal dysregulation with aberrant aromatase activity, and altered adipogenesis (peroxisome proliferator-activated receptor gamma [PPARγ], CCAAT/enhancer-binding protein [C/EBP]). A proinflammatory microenvironment with macrophage M1/M2 imbalance, elevated interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and extracellular matrix remodeling is hypothesized to drive fibrosis. Emerging evidence implicates gut-derived endotoxemia (lipopolysaccharide [LPS]-toll-like receptor 4 [TLR4]-nuclear factor kappa-B [NF-κB]) and mechanotransduction (Yes-associated protein [YAP]/transcriptional coactivator with PDZ-binding motif [TAZ]) in adipocyte hypertrophy and treatment resistance. Obesity involves systemic metabolic dysfunction with visceral adiposity and cardiometabolic comorbidities. Lipedema patients maintain metabolic health, exhibit gluteofemoral fat distribution and experience neuropathic pain via nociceptor sensitization (transient receptor potential vanilloid 1 [TRPV1] and ankyrin 1 [TRPA1]) with central amplification. Weight-loss interventions are ineffective, necessitating targeted strategies. Promising targets include TLR4 antagonism, vascular endothelial growth factor C/vascular endothelial growth factor receptor-3 (VEGF-C/VEGFR3) modulation for lymphatic enhancement, YAP/TAZ inhibition and neuromodulators for pain. Physical therapy functions as a biological modifier targeting inflammation, lymphatic drainage and mechanotransduction. This review highlights promising but largely hypothesis-generating molecular insights and calls for validated biomarkers, rigorous clinical trials, and mechanism-based therapies. Many of the pathways discussed require further confirmation in human studies.

Background: Lipedema is a chronic disorder of subcutaneous adipose tissue characterized by symmetrical fat accumulation in the extremities, pain, and orthostatic edema. Objectives: This study aimed to assess whether high-resolution cutaneous ultrasound can detect measurable tissue-level changes in subcutaneous tissue over six months. Methods: A retrospective, single-center, real-world longitudinal observational cohort study was conducted in 60 women with lipedema followed at three timepoints (baseline, 3 months, 6 months). High-resolution ultrasound (18–20 MHz) measured subcutaneous and dermal thickness at standardized anatomical sites. Results: All primary ultrasound parameters decreased significantly over six months of conservative multicomponent management, which included individualized nutritional counseling and physical activity. Medial proximal thigh subcutaneous thickness declined by 18.7% (48.2 to 39.2 mm; p < 0.001). Edema prevalence fell from 100% to 55.0%. Echogenicity improved significantly between 3 and 6 months, suggesting a delayed structural remodelling effect distinct from early volumetric reduction. Ultrasound reductions were inversely correlated with weight loss, suggesting that ultrasound captures tissue-level information not fully reflected by anthropometric measures alone. Conclusions: Standardized cutaneous high-resolution ultrasound detected consistent tissue-level modifications over six months of routine clinical follow-up, capturing changes beyond anthropometric measures and representing a candidate monitoring tool warranting evaluation in controlled study designs.

Background: Lipedema is a chronic progressive condition affecting approximately 10% of women, characterized by disproportionate subcutaneous adipose tissue accumulation and pain in the lower extremities. Standardized assessment methods for pain evaluation in lipedema remain limited. The Progressive Pain Check (PPC) method represents a potentially valuable tool for standardized pain assessment in lipedema patients. Objective: To evaluate the inter-rater reliability of the PPC method for clinical assessment of evoked pain in lipedema patients. Methods: Two independent assessors performed PPC evaluations. Inter-rater reliability was assessed using the Intraclass Correlation Coefficient [ICC(2,1), two-way random-effects, absolute agreement, single-measurement] with 95% confidence intervals (CI). Results: This study included 429 women diagnosed with lipedema (mean age 41.2 ± 11.5 years, mean disease duration 27.2 ± 12.6 years). Patient characteristics revealed mean BMI of 29.5 ± 6.9 kg/m2, predominantly Type III lipedema presentation, and disease onset during adolescence (mean age 14 ± 9.3 years). The PPC method demonstrated excellent inter-rater reliability between two independent assessors across all examined anatomical districts. Conclusions: The PPC method shows promise as a simple, repeatable, and standardized clinical tool for evoked pain assessment in lipedema patients. The demonstrated inter-rater reliability supports its potential utility in clinical practice. Further research is warranted to evaluate its intra-rater reliability, concurrent validity, and responsiveness in monitoring treatment effects.

Lower extremity swelling has a broad differential diagnosis, including lymphedema, obesity-induced lymphedema, phlebolymphedema, and lipedema. Although these conditions may appear similar clinically, their pathophysiology and lymphoscintigraphic findings differ. Obesity, venous insufficiency, and abnormal adipose tissue can complicate image interpretation. We present four representative cases to illustrate characteristic imaging patterns across these conditions. These cases highlight the importance of interpreting lymphoscintigraphy in a clinical context.

BACKGROUND: Lipedema is a chronic disorder characterized by excessive, bilateral, and symmetrical deposition of subcutaneous adipose tissue, predominantly in the lower extremities. Despite its prevalence, lipedema is frequently misdiagnosed as lymphedema, and lymphoscintigraphy is commonly used to differentiate between the two. This systematic review synthesizes the available evidence regarding the most common lymphoscintigraphy findings in patients with lipedema. METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed across the MEDLINE/PubMed, Embase, and Web of Science databases. Studies were included if they reported lymphoscintigraphy findings in patients with lipedema and provided a clear description of the imaging protocol. Extracted data included patient demographics, lymphoscintigraphy protocols, and imaging findings. RESULTS: Seven studies met the inclusion criteria, encompassing 470 patients, of whom 311 had lipedema. The mean age was 47.4 years, and all patients were women. The mean body mass index was 32.6 kg/m2. Lymphoscintigraphy findings were normal in 61.4% of patients with lipedema. Tortuous lymph vessels were the most common abnormality (56.8%), followed by collateral lymph vessels (49.1%) and popliteal node visualization (44.0%). Dermal backflow (3.8%) and secondary lymphedema (11.8%) were less frequent. CONCLUSIONS: Lymphoscintigraphic alterations in patients with lipedema seem to reflect lymphatic overload rather than frank insufficiency. However, significant heterogeneity in study methodologies precluded a quantitative meta-analysis. Future research should focus on establishing standardized, consensus-based imaging protocols to better define the role of lymphoscintigraphy in the diagnosis and staging of lipedema.

Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation.

Background: Lipedema is a chronic disorder that predominantly affects women and is characterized by abnormal subcutaneous adipose tissue accumulation, pain, and vascular dysfunction. However, reliable circulating biomarkers that reflect disease-specific pathophysiology are still lacking. This study investigated serum markers associated with adipose tissue, inflammation, and angiogenesis to further elucidate the pathophysiology of lipedema. Methods: In this cross-sectional observational study, fasting serum levels of adiponectin, chemerin, lipopolysaccharide-binding protein (LBP), proprotein convertase subtilisin/kexin type 9 (PCSK9), soluble CD163 (sCD163), and soluble CD137 (sCD137)—proteins associated with obesity and inflammation—were measured in 23 premenopausal women with lipedema and 23 age-matched healthy premenopausal controls. Serum endostatin levels, an angiogenesis inhibitor, and insulin-like growth factor binding protein 2 (IGFBP2), a potent proangiogenic factor, were also assessed. Results: Patients with lipedema and obese controls had comparable body mass index, glucose, and serum lipid profiles. No significant differences were observed between groups in circulating levels of adiponectin, chemerin, LBP, PCSK9, sCD163, sCD137 and IGFBP2. In contrast, serum endostatin levels were significantly reduced in patients with lipedema (p = 0.038). Additional analyses demonstrated markedly higher endostatin expression in human subcutaneous adipose tissue than in the liver, suggesting that circulating endostatin levels may be related to adipose tissue mass. However, serum endostatin levels were lower in obese compared with normal-weight women (p < 0.001). Conclusion: Lipedema was not associated with altered circulating levels of adiponectin, chemerin, LBP, PCSK9, sCD163, sCD137 or IGFBP2. Reduced serum endostatin levels support a potential role for vascular dysfunction in the pathophysiology of lipedema.

Lipedema is a chronic disorder of subcutaneous adipose tissue characterized by disproportionate fat accumulation, pain, and progressive functional impairment, predominantly affecting women. Research remains fragmented across vascular, hormonal, metabolic, and gynecologic perspectives. Recent contributions have advanced specific axes: an international Delphi consensus, a systematic review of hormonal hypotheses, a stromal-vulnerability narrative, and a focused review of adipose biology; but no prior framework has integrated these domains into a single architecture annotated by level of evidence and capable of generating stratified, falsifiable research hypotheses. Here, we propose a hypothesis-generating translational framework that conceptualizes lipedema as the predominant adipose expression of a hormone-sensitive stromal vulnerability. The framework adds a specific molecular convergence axis, ERα/ERβ signaling imbalance interacting with intracrine steroid metabolism (aromatase, 17β-HSDs, AKR1C1), and resolves the disorder into four interacting biological pathways: (i) hormonal transition sensitivity across the female life course; (ii) metabolic– behavioral amplification; (iii) gynecologic–endocrine comorbidity; and (iv) intrinsic stromal–adipose susceptibility. The framework predicts that lipedema and its cognate expressions in hormone-responsive tissues (including gynecologic disease, connective tissue laxity, microvascular dysfunction, neurosensory amplification, and neuropsychological burden) may share a common stromal-endocrine substrate while preserving phenotypic specificity through dominant-pathway combinations. Four features distinguish this framework from prior syntheses: (a) ERα/ERβ signaling imbalance is articulated as a candidate molecular convergence axis linking adipose, gynecologic, connective-tissue, microvascular, and neuro-immune manifestations; (b) intracrine steroid metabolism (aromatase, 17β-HSDs, AKR1C1) is incorporated as the mechanistic anchor of stromal hormone-responsiveness; (c) per-component evidence-level annotation is applied throughout (Level 1A/1B: direct evidence in lipedema; Level 2: observational association; Level 3: mechanistic extrapolation); and (d) stratified, falsifiable research hypotheses are derived from dominant-pathway phenotypes. Two domains, metabolic burden and steroid signaling, emerge as promising translational research domains. Important limitations apply. Direct mechanistic evidence in lipedema-specific tissues is limited; much of the supporting biology is extrapolated from adipose, gynecologic, and metabolic literatures; and most clinical data derive from observational cohorts in referral centers. This article therefore proposes a hypothesis-generating translational framework, not a clinical guideline or therapeutic recommendation.

Objectives: To examine the associations of ultra-processed food (UPF) consumption, dietary inflammatory index (DII), and Mediterranean diet adherence with pain severity, physical quality of life, body composition, and inflammatory markers in women with lipedema. Methods: This cross-sectional study included women diagnosed with lipedema across different disease stages. Dietary intake was assessed using a validated food frequency questionnaire, and foods were classified according to the NOVA system to determine UPF consumption. The dietary inflammatory index was calculated to assess the inflammatory potential of the diet, and Mediterranean diet adherence was evaluated using a standardized scoring system. Anthropometric measurements, body composition parameters, inflammatory markers, pain intensity (VAS), and physical quality of life (SF-12 PCS) were assessed. Multivariable regression analyses were performed to investigate the associations between dietary variables and clinical outcomes. Results: A total of 86 women with lipedema (stage 1: n=36, stage 2: n=33, stage 3: n=17) were included. UPF consumption increased from 28.1% to 41.3% of total energy and DII scores from +1.46 to +3.02 across stages, while Mediterranean diet adherence decreased from 28.2 to 21.3. In parallel, BMI increased from 27.1 to 31.1 kg/m² and body fat percentage from 36.7% to 41.1%. Inflammatory markers also rose across stages (hs-CRP: 3.9 to 6.1 mg/L; IL-6: 3.1 to 4.6 pg/mL). In multivariable models, higher DII scores were associated with increased pain severity (β=0.29, p=0.007) and higher hs-CRP levels (β=0.41, p<0.001), whereas Mediterranean diet adherence was positively associated with physical quality of life (β=0.34, p=0.002). Conclusion: Higher ultra-processed food consumption and dietary inflammatory potential were associated with increased inflammation, pain, and adiposity, whereas greater Mediterranean diet adherence was associated with better physical quality of life in women with lipedema.

BACKGROUND: Lipedema is a chronic and progressive adipose tissue disorder that is often misdiagnosed and notoriously resistant to weight loss. Liposuction remains the most effective surgical treatment, but it requires precise technique to preserve the fragile lymphatic system. This study investigates the utility of pre-, intra- and postoperative ultrasound (US) to objectively assess fat reduction and the selective removal of pathological adipose tissue in patients undergoing liposuction for lipedema. METHODS: A retrospective, single-center study of 24 female patients with lipedema who underwent liposuction of the lower extremities. Perioperative US was used to measure the thickness of the superficial subcutaneous fat (D1) and the deep fat layer (D2) at a standardized anatomical site. Intraoperative US was employed to verify that fat aspiration was performed in the correct superficial plane. A paired t-test was conducted to assess the statistical significance of the change in D1 thickness. RESULTS: The mean patient age was 38 years, with a mean BMI of 25.3 kg/m2. The mean volume of liposuction aspirate was 4.5 L. Statistical analysis showed a significant reduction in mean D1 thickness from 9.9 mm preoperatively to 6.3 mm immediately postoperatively (p < 0,05). This reduction was sustained at the 3-month follow-up, with a mean D1 thickness of 5.8 mm. CONCLUSION: Our pilot study suggests that the perioperative use of ultrasound is a valuable tool for objectively documenting the selective fat reduction achieved with liposuction in lipedema patients. Intraoperative US not only enhances surgical precision, but also reduces the risk of complications by confirming correct cannula positioning in the superficial plane. This technique enhances surgical precision by allowing for the quantifiable removal of pathological superficial fat, confirming its potential to improve outcomes with a low complication rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Lipedema has long been misclassified as a cosmetic concern or a subtype of obesity, leading to delayed diagnosis and suboptimal surgical outcomes. Growing molecular, histopathologic, and imaging evidence supports lipedema as a systemic disorder involving adipose tissue, connective matrix, vascular–lymphatic integrity, and neuroimmune regulation. To integrate these findings into a clinically actionable model, we introduce the concept of Adipoconnective Fragility Syndrome (AFS), framing lipedema as a multisystem condition with direct implications for surgical planning and perioperative management.

Background/Objectives: Lipedema is a chronic adipose tissue disorder characterized by disproportionate fat accumulation, pain, microvascular dysfunction, and low-grade inflammation. Although low-carbohydrate, high-fat (LCHF) dietary approaches are increasingly used in clinical practice, their longer-term associations with vascular, lymphatic, and immunometabolic pathways in lipedema remain insufficiently understood. This preliminary exploratory study evaluated clinical outcomes and circulating mediators during a 7-month LCHF dietary intervention. Methods: Twenty-four women with lipedema (median age: 39 years) underwent a 7-month individualized, calorie-restricted LCHF diet under medical supervision. Outcomes included body mass index (BMI), leg volume, and adipose tissue pain assessed using a visual analogue scale (VAS). Fasting serum samples collected at baseline and follow-up were analyzed for angiogenic, inflammatory, endothelial, and lipid mediators using Luminex assays and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: The intervention was associated with significant reductions in BMI, leg volume, and adipose tissue pain (p < 0.001). These changes were accompanied by increased vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor D (VEGF-D), and angiopoietin-2 (Ang-2), together with decreased pro-inflammatory cytokines and endothelial adhesion molecules. Several endocannabinoid-related lipid mediators, including oleoyl ethanolamide (OEA), arachidonoyl ethanolamide (AEA), and palmitoyl ethanolamide (PEA), also decreased. Baseline OEA and AEA concentrations, as well as reductions in OEA over time, were associated with greater BMI reduction. Change in interleukin-8 (IL-8) showed a nominal association with leg volume reduction, while pain improvement was associated with decreases in P-selectin and VEGF-A and increases in interleukin-13 (IL-13). Conclusions: A 7-month calorie-restricted LCHF dietary intervention in women with lipedema was associated with clinical improvement and changes in circulating vascular, inflammatory, and lipid mediators. These findings reflect systemic changes accompanying the intervention; however, causal relationships and specific mechanisms cannot be established.

Lipedema is a chronic and progressive adipose tissue disorder characterized by disproportionate fat accumulation, microvascular dysfunction, chronic inflammation, and progressive fibrosis. Despite its prevalence and significant impact on quality of life, current therapeutic approaches remain largely symptomatic and fail to address the underlying biological mechanisms of the disease. Emerging evidence suggests that lipedema should be understood as a multifactorial condition involving genetic susceptibility, endothelial alterations, immune dysregulation, and extracellular matrix remodeling. In this context, pharmacological strategies targeting these pathways have gained increasing attention. Metformin, through activation of AMP-activated protein kinase (AMPK), exerts antifibrotic and immunometabolic effects, including inhibition of TGF-β signaling, reduction of extracellular matrix deposition, and modulation of adipose tissue inflammation. In parallel, incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP agonists such as tirzepatide, have demonstrated pleiotropic effects that extend beyond weight reduction, including improvements in metabolic homeostasis, reduction of systemic inflammation, and enhancement of endothelial function. These therapies appear to act through complementary mechanisms, with metformin primarily targeting tissue remodeling and fibrosis, and incretin-based therapies exerting broader systemic effects on metabolism, inflammation, and vascular integrity. This review proposes a hypothesis-generating mechanistic framework, supporting a shift from weight-centric and symptomatic approaches toward disease-modifying strategies. Although current evidence in lipedema is largely indirect, the convergence of experimental and clinical data provides a strong rationale for further investigation. Future studies should focus on evaluating combined therapeutic approaches and identifying biomarkers that reflect fibrosis, inflammation, and microvascular dysfunction, with the aim of developing targeted and personalized treatments for this complex disorder.

Infragluteal deformities are a challenging complication following liposuction, particularly when injury occurs to the fibrous osteocutaneous bands of the gluteal crease. Various surgical solutions have been proposed, including autologous fat grafting, skin-lifting procedures, and flap reconstructions, yet a consistent, scar-free, and minimally invasive technique remains elusive. In this report, we present a new modified net suture technique, inspired by the hemostatic net used in aesthetic facial surgery, as a promising treatment for post-liposuction infragluteal deformities. After aggressive power-assisted liposuction to detach mispositioned adhesions within the gluteal crease, we apply a transcutaneous continuous-running suture using non-absorbable nylon, fixed along the newly established crease. The suture is laid loosely to preserve skin perfusion, cushioned by an ointment dressing, and supported with external compression. The technique is completed in approximately 15 minutes, with suture removal on postoperative day 4. In our experience, this approach leads to aesthetically satisfactory outcomes, restores gluteal symmetry, and avoids the formation of additional scars. Our technique is simple, cost-effective, and preserves lymphatic and vascular integrity. This manuscript describes our methodology, rationale, and early clinical observations supporting this low-risk intervention.