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Lipedema in its various clinical stages is a condition that almost exclusively affects the female sex and appears at puberty. The oedema does not respond to common low-calorie diets, nor to exercise, nor to common anti-oedema medical therapies, nor to bariatric surgery. In the more advanced clinical stages, it can induce more or less important functional impairments that induce physical disability, as well as psychological, relational, and social discomfort: pain, functional walking impotence, easy muscular fatigability, sleep-wake rhythm disturbances also linked to the state of anxiety and depression that affects subjects in whom, often, the response to the treatments they are directed towards is practically nil. Many epidemiological, aetiopathogenetic, diagnostic, and clinical aspects still need to be studied in depth, considering, moreover, that the disease was only recognized with its own specific code by the World Health Organization in the 11th edition of the International Classification of Diseases on 1 January 2022.

Lipedema is a chronic, progressive disorder of adipose tissue that predominantly affects women, characterized by symmetrical fat accumulation in the extremities, pain, and resistance to caloric restriction. Recent insights suggest that lipedema represents a hormone-driven gynecological fat disorder, in which estrogen receptor (ER) imbalance plays a central role. The predominance of ERβ activity and suppression of ERα signaling are hypothesized to drive adipose hypertrophy, fibrosis, and inflammation, particularly in the context of intracrine estradiol excess. This model aligns lipedema with other estrogen-sensitive conditions, such as endometriosis and uterine fibroids, and provides a novel framework for understanding its pathophysiology. Therapeutically, this reframing opens new perspectives for hormonal modulation using selective progestins (drospirenone, gestrinone) and metabolic adjuncts such as tirzepatide, beyond the current symptomatic or surgical approaches.

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized by enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance in adipose tissue mass and adipose tissue distribution. In 1951 a second seminal paper provided more description of lipedema. Fat distribution involves the lower extremities, upper arms, hips, buttocks, thighs, sparing trunks, and feet. Lower extremities are characterized by pain, easy bruisability, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized by enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance in adipose tissue mass and adipose tissue distribution. In 1951 a second seminal paper provided more description of lipedema. Fat distribution involves the lower extremities, upper arms, hips, buttocks, thighs, sparing trunks, and feet. Lower extremities are characterized by pain, easy bruisability, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.

Often regarded as the forgotten second circulatory system, the lymphatic system is critical in working with the venous and arterial system to maintain fluid equilibrium, circulate cells and signaling molecules in the immune system, and transport fat molecules and nutrients. When there is an alteration in the flow of lymphatic fluid, lymphedema is the result, usually manifesting as significant swelling of a particular region of the body with protein-rich fluid accumulation in the interstitial spaces. The result of this disease ranges from psychological disturbance to significant disability and morbidity, even leading to aggressive malignancy. The prevalence of lymphedema is in the hundreds of millions worldwide; however, it is routinely under-diagnosed and under-recognized as a disease, especially in the United States. Treatment rates for lymphedema are variable, ranging from low rates of treatment in non-cancer etiologies, to high treatment rates seen in breast cancer related etiologies. Furthermore, treatment modalities are equally notorious for being unsuccessful, either as a result of non-compliance or lack of efficacious therapeutic techniques, or a combination of both. There is no cure for lymphedema and treatment mainly focuses on minimizing limb swelling, maintaining functionality, and preventative treatments to reduce complications.

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized as enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance in adipose tissue mass and adipose tissue distribution.[1][2][3][4] In 1951 a second seminal paper provided more description of lipedema. Fat distribution involves lower extremities, upper arms, hips, buttocks, thighs sparing trunks, and feet.[2] Lower extremities are characterized by pain, easy bruisability, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.[5][6]

Lipedema is an underdiagnosed painful adipose tissue disorder that occurs almost exclusively in women, with onset manifesting at puberty or at times of hormonal change. Unlike many fat disorders, diet and exercise have little to no impact on the prevention or progression of this disease. Estrogens control the distribution of body fat and food intake, regulate leptin expression, increase insulin sensitivity, and reduce inflammation through signaling pathways mediated by its receptors, estrogen receptor alpha (ERα) and ERβ. This review will focus on understanding the role of estrogen in the pathogenesis of the disease and envisage potential hormonal therapy for lipedema patients.

Lipedema is a painful fat disease of loose connective tissue usually misdiagnosed as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations. Lipedema is characterized by symmetric enlargement of the buttocks, hips, and legs due to increased loose connective tissue; arms are also affected in 80% of patients. Lipedema loose connective tissue is characterized by hypertrophic adipocytes, inflammatory cells, and dilated leaky blood and lymphatic vessels. Altered fluid flux through the tissue causes accumulation of fluid, protein, and other constituents in the interstitium resulting in recruitment of inflammatory cells, which in turn stimulates fibrosis and results in difficulty in weight loss. Inflammation and excess interstitial substance may also activate nerve fibers instigating the painful lipedema fat tissue. More research is needed to characterize lipedema loose connective tissue structure in depth, as well as the form and function of blood and lymphatic vessels. Understanding the pathophysiology of the disease will allow healthcare providers to diagnose the disease and develop treatments.

Lipedema is a chronic fat disorder with disproportional fat distribution, especially around the legs, hips, and sometimes arms, and it affects women almost exclusively. The major symptoms and complaints include pain in the soft tissue and the feeling of “heavy legs.” The perception of pain depends to a high degree on the psychological condition of the patient. Obesity is the major comorbidity and can worsen lipedema. In combination with impaired levels of physical activity, there is an increase in interstitial filtration, and noninfectious inflammation with capillary leakage can occur. Eventually, chronic edema develops due to the dynamic insufficiency of the lymphatic system. However, edema is not a pathognomonic aspect of lipedema. There are many controversies and myths about the condition lipedema, and no objective diagnostic tool is available to confirm the diagnosis. Therapeutic approaches in lipedema are multimodal and focus on the biomedical, psychological, and functional aspects involved with the disorder. A lifestyle change is often part of the therapeutic program, along with other therapeutic interventions, such as exercise, compression, weight management, and nutritional and psychological support. Clinimetrics with validated techniques in all fields of human functioning of a lipedema patient are mandatory to objectively evaluate the improvements that are due to the treatment program. Liposuction is a technique to remove fat and is therefore introduced to treat lipedema. Some doctors who offer the procedure state that “liposuction leads to comprehensive and long-term improvements in lipedema and cures the disease.” These statements are often too optimistic and lead to high costs for the patient and disappointment in the end. However, liposuction can lead to improvements in lipedema when offered within a therapeutic program that includes other nonoperative modalities for the correct selection of patients according to their medical criteria. It cannot be emphasized enough that liposuction is not a method that should be used to treat obesity.

Subcutaneous adipose tissue diseases involving adipose tissue and its fascia, also known as adipofascial disorders, represent variations in the spectrum of obesity. The adipofascia diseases discussed in this chapter can be localized or generalized and include a common disorder primarily affecting women, lipedema, and four rare diseases, familial multiple lipomatosis, angiolipomatosis, Dercum disease, and multiple symmetric lipomatosis. The fat in adipofascial disorders is difficult to lose by standard weight loss approaches, including lifestyle (diet, exercise), pharmacologic therapy, and even bariatric surgery, due in part to tissue fibrosis. In the management of obesity, healthcare providers should be aware of this difficulty and be able to provide appropriate counseling and care of these conditions. Endocrinologists and primary care providers alike will encounter these conditions and should consider their occurrence during workup for bariatric surgery or hypothyroidism (lipedema) and in those that manifest, or are referred for, dyslipidemia or diabetes (Dercum disease). People with angiolipomas should be worked up for Cowden’s disease where a mutation in the gene PTEN increases their risk for thyroid and breast cancer. This chapter provides details on the pathophysiology, prevalence, genetics and treatments for these adipofascial disorders along with recommendations for the care of people with these diseases. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

The easiest way to differentiate lipedema from lymphedema is to detect lipedema-associated clinical symptoms (e.g., cuffing sign, retromalleolar fat pads, tenderness of the skin). Physical examinations including the Streeten test, waist-to-height ratio, capillary fragility, and pain measurements can also aid in differential diagnosis. The last two methods can be used to follow and measure therapeutical efficacy. Imaging techniques (ultrasound, computed tomography, magnetic resonance imaging, lymphoscintigraphy, infrared fluoroscopy) and cardiovascular methods (aortic stiffness determination, three-dimensional speckle tracking echocardiography) are sensitive tools to find subtle differences.

Lipedema is an infrequently recognized and often neglected clinical entity that nearly always affects women. It poses a diagnostic challenge as one of the common disorders that is easily confused with lymphedema.