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BACKGROUND: Lipedema is a chronic, progressive adipose tissue disorder that predominantly affects women and is characterized by disproportionate fat accumulation, pain, and edema. Hormonal fluctuations are frequently reported as triggers or modulators of symptoms, but the impact of exogenous hormones, especially hormonal contraceptives, remains poorly defined. OBJECTIVE: This study aimed to investigate the association between hormonal contraceptive use and the presence, severity, and self-reported worsening of lipedema symptoms in Brazilian women. METHODS: This observational, cross-sectional study was conducted at Amato - Instituto de Medicina Avançada using a structured online questionnaire applied between August and November 2025. We included women aged 18 years or older, residing in Brazil, with suspected or confirmed lipedema who provided electronic consent and completed core sections on lipedema symptoms, hormonal history, and contraceptive use. Questionnaires with less than 50% of core items answered, duplicate entries, and biologically implausible values were excluded. Symptom (0-8) and quality of life (0-15) scores were calculated. Self-reported changes in symptoms after starting hormonal contraceptives were analyzed as a four-level variable and as a binary worsening variable. Free text on side effects and timing of onset was categorized with natural language processing. Statistical analyses included chi-squared tests, Spearman correlations, and logistic and linear regression. RESULTS: A total of 637 women were included (mean age 41.8±8.7 years; mean body mass index (BMI) 28.9±6.4 kg/m²); 77.1% had a confirmed diagnosis of lipedema and 92.3% were current or previous users of hormonal contraceptives. Among users, 58.8% reported symptom worsening after starting contraceptives (34.5% severe; 24.3% slight), 40.3% reported no change, and 0.9% reported improvement (p<0.001). Free text analysis showed that 15.1% reported onset of lipedema symptoms temporally coinciding with contraceptive initiation. In multivariable analysis, a higher baseline symptom score was the strongest independent predictor of worsening, while duration of contraceptive use was not associated with risk. Pain intensity and BMI were the main independent predictors of quality of life impact. CONCLUSIONS: In this large sample of Brazilian women with suspected or confirmed lipedema, hormonal contraceptive use was frequently associated with self-reported worsening of symptoms, and a substantial minority reported symptom onset around contraceptive initiation. Women with higher baseline symptom burden appeared particularly vulnerable. These findings support individualized contraceptive counseling for women with lipedema and highlight the need for prospective studies with objective measures to clarify causality and mechanisms.

Background Lipedema is characterized by disproportionate gluteofemoral adiposity with anti-inflammatory properties. We hypothesized that this phenotype may confer immunological protection against T-helper 1 (Th1)-mediated autoimmunity ("Immunological Shield Hypothesis"). Objective The objective of this study is to explore whether women with a dual-energy X-ray absorptiometry (DXA)-defined lipedema-like phenotype, characterized by disproportionate gluteofemoral fat accumulation, exhibit distinct immunometabolic profiles and lower prevalence of celiac disease (CD) autoimmunity in a nationally representative sample. Methods The cross-sectional analysis included 3,833 women from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Celiac disease (n=11, 0.56% weighted prevalence) was defined by strict serology (tissue transglutaminase {tTG}-IgA+/endomysial antibody {EMA}-IgA+); lipedema phenotype was defined as leg-to-trunk fat ratio of >90th percentile via DXA. Results Women with celiac disease exhibited 7.4% lower gynoid fat (39.5% versus 42.6%, p=0.0007), persisting in overweight/obese strata. Conversely, the lipedema phenotype demonstrated superior metabolic health: 44.2% lower homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.001) and 7.6% lower neutrophil-to-lymphocyte ratio (NLR) (p=0.012). Conclusions This exploratory population-based analysis identifies phenotypic divergence in fat distribution between the DXA-defined lipedema phenotype and celiac disease autoimmunity, yielding observations consistent with, but not confirmatory of, the "Immunological Shield Hypothesis." While limited by the small number of celiac cases (n=11), a sample size insufficient to detect prevalence differences for a ~7%-9% phenotype, for which approximately 225-600 celiac cases would be required, the observed differences in gynoid adiposity (7.4% reduction, p=0.0007) and the favorable metabolic profile of the lipedema phenotype (44.2% lower HOMA-IR and 7.6% lower NLR) suggest biological plausibility warranting validation in larger, targeted cohorts. These findings motivate targeted studies to evaluate whether dietary exposures, including gluten-related immune activation, interact with gluteofemoral adipose biology in lipedema.

Background: Lipedema is a common, female-predominant disorder characterized by disproportionate, painful lower-limb adipose tissue, and it still lacks an objective biomarker, a disease-modifying therapy, or consensus on whether its core lesion is inflammatory. Its molecular literature is openly contradictory, reporting both immune enrichment and immune down-regulation in the same gluteofemoral depot. Because the dominant morbidity is pain rather than adipose mass, this ambiguity carries direct clinical cost. We therefore asked the following three questions: whether the reported molecular hallmarks survive control for cell-type composition, whether pain and adipose volume behave as separable endpoints, and what the germline architecture implies about the primary lesion. Materials and methods: From a theory-neutral standpoint, we reprocessed the largest publicly deposited adipose bulk RNA-seq dataset of lipedema (14 women with lipedema versus seven controls, paired by depot) with Salmon (College Park, MD: University of Maryland) and DESeq2 (Seattle, WA: Bioconductor Project), estimated cell-type composition by single-sample gene-set enrichment (ssGSEA), and refitted differential expression with leukocyte and erythroid composition covariates to test identifiability. We also synthesized published treatment cohorts (pain versus volume) and reviewed the architecture of germline genome-wide association studies (GWAS). Results: There is no transcriptional lipolytic brake (ADRA2A +0.001; lipases unchanged or mildly up). The apparent immune down-regulation is not identifiable from blood content; adjusting for tissue composition reduces genome-wide-significant genes from 1,501 to four, with blood content correlated with disease at r approximately -0.7, so bulk data can neither establish nor exclude immune involvement, including the NLRP3 inflammasome. Pain and adipose volume are dissociable across treatments, so body weight is a confounded endpoint. The germline architecture reported to date (GRB14-COBLL1, VEGFA, RSPO3, ADAMTS9) is adipo-vascular and extracellular-matrix-based rather than immune, although the largest contributing study defined cases by a bioimpedance proxy rather than by clinical diagnosis. Conclusions: Lipedema's inflammatory status is currently undecidable from composition-confounded bulk tissue rather than settled, which explains the field's contradictory literature; the germline evidence, limited by its case definitions, supports as a hypothesis an adipo-vascular and connective program rather than a primary immune lesion; and pain, not weight, should anchor trials. We specify, but do not perform, the single decisive experiment - paired thigh-versus-abdomen single-nucleus RNA-seq with explicit composition control.

Objective The aim of this study is to assess the prevalence of HLA-DQ2 and HLA-DQ8 in women diagnosed with lipedema. Methods Leukocyte histocompatibility antigen (HLA) tests of 95 women diagnosed with lipedema were analyzed using non-probabilistic sampling for convenience. The prevalence of HLA-DQ2 and HLA-DQ8 was compared to the general population. Results The prevalence of HLA-DQ2+ was 47.4%, that of HLA-DQ8+ was 22.2%, the presence of any celiac disease associated HLA (HLA-DQ2+ or HLA-DQ8+) was 61.1%, both HLA (HLA-DQ2+ and HLA-DQ8+) was 7.4%, and the absence of celiac disease associated HLA was 39%. Compared to the general population, there was a significantly higher prevalence of HLA-DQ2, HLA-DQ8, any HLA, and both HLAs in lipedema patients. The mean weight of patients with HLA-DQ2+ was significantly lower than the overall study population, and their mean BMI significantly differed from the overall mean BMI. Conclusion Lipedema patients seeking medical assistance have a higher prevalence of HLA-DQ2 and HLA-DQ8. Considering the role of gluten in inflammation, further research is needed to establish if this association supports the benefit of gluten withdrawal from the diet in managing lipedema symptoms.

Hyperechoic subcutaneous nodules in lipedema may mimic angiolipomas but represent an inflammatory and hypoxic-ischemic process rather than a neoplasia, despite tissue expansion. As the painful nodules expand, biopsy is recommended to exclude cancer. In this context, ultrasound (US) has become a pivotal tool for diagnosing and managing these nodules when combined with histopathologic assessment. However, many professionals in the field still have limited knowledge of this topic. In the present case series, the US and histopathologic findings of hyperechoic nodules in two patients with lipedema were compared with those observed in two patients with angiolipoma, with the aim of proposing US criteria to distinguish between these entities and highlighting the importance of accurate differential diagnosis.