Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and NIH Women's Health Research

Signs, Symptoms, and Risk Factors

ME/CFS is a serious, long‑term, and multisystem illness. It is characterized by severe functional impairment and fatigue that is not improved by rest, unrefreshing sleep, and a hallmark symptom known as postexertional malaise.^{1 - 6} Other symptoms include cognitive impairment, orthostatic intolerance, joint and muscle pain and weakness, dizziness, headache, and digestive issues; these symptoms often fluctuate in severity and duration.^{1 , 2 , 4 , 5} Before the COVID-19 pandemic, ME/CFS was estimated to affect up to 3.3 million people in the United States.^{3 , 6} More recent estimates, which include cases associated with post-COVID ME/CFS, suggest that the number may have risen to 18 to 26 million U.S. adults.^{7 , 8} ME/CFS is often disabling, leaving some individuals homebound or bedbound.^{1 - 3 , 5 , 6 , 9} Because there is no single diagnostic test for ME/CFS and symptom presentation varies, many cases remain undiagnosed, even when the condition causes significant functional limitations.

Although the exact cause of ME/CFS remains unknown, multiple potential triggers and risk factors have been identified. About 10% of people who have certain infections (e.g., those caused by the Epstein-Barr virus or Coxiella burnetii) develop ME/CFS, and many people with post-acute sequelae of SARS-CoV-2 infection (long COVID) meet the criteria for or have symptoms that are similar to ME/CFS.^{2 , 6} Other contributors may include immune system changes, major physical or emotional stress or trauma, differences in cellular energy production, and genetic predisposition.^{1 , 2 , 6} Conditions that are comorbid with ME/CFS can include , irritable bowel syndrome, sleep disorders, metabolic syndrome, mast cell disorders, depression, and postural orthostatic tachycardia syndrome (POTS).^{6 , 9} ME/CFS is most commonly identified in middle‑aged adults, particularly those between 40 and 60 years of age, but some individuals may present at an earlier age, and there are a significant number of cases in children.

Impact on Women's Health

Women are two to four times more likely to develop ME/CFS than men.^{1 - 3 , 5 , 10} In addition, women experience a more severe symptom burden than men, including greater functional impairment; more frequent pain, morning stiffness, muscle cramps, and dizziness; and a poorer quality of life.¹¹ The underlying reasons for these sex disparities are not fully understood and are being explored; hypotheses include hormonal influences and differences in gene expression and immune responses. For example, a small retrospective study of plasma samples from the UK ME/CFS Biobank found differences in circulating steroid hormone levels that were stratified by sex and severity of disease across individuals with ME/CFS and healthy individuals.¹² Another small pilot study found that biologic sex influences differential gene expression of peripheral blood mononuclear cells during exercise and recovery in individuals with ME/CFS.¹³ In addition, a study conducted by the Centers for Disease Control and Prevention (CDC) found that several gynecologic factors were positively associated with the incidence of ME/CFS in women, including a younger age at the onset of menopause, excessive menstrual bleeding, bleeding between periods, endometriosis, and gynecological surgeries (e.g., hysterectomy).¹⁴

Diagnosis and Treatment

Because no confirmatory laboratory test for ME/CFS currently exists, diagnosis is based on a thorough medical history, physical examination, and a targeted work-up, and other potential causes must be ruled out.^{5 , 6 , 9 , 15} According to the diagnostic criteria established by the Institute of Medicine in 2015, an ME/CFS diagnosis requires evidence of substantial and persistent functional impairment that lasts more than 6 months and that is accompanied by new‑onset fatigue, postexertional malaise, and unrefreshing sleep. Individuals with ME/CFS must also exhibit either cognitive impairment or orthostatic intolerance. These characterizing symptoms must be present at a moderate or higher severity at least 50% of the time.⁶ The CDC has an assessment overview that can assist clinicians in the diagnosis of ME/CFS.¹⁶

Postexertional malaise is considered to be the hallmark feature of ME/CFS. It is defined as a profound, multi-symptomatic flare that occurs after physical, cognitive, or emotional exertion that was previously tolerated, and it typically occurs hours to days after the overexertion.^{17 , 18} Individuals who experience active postexertional malaise episodes from ME/CFS are unable to perform even basic functions without significant difficulty. If a person with ME/CFS is forced to push through postexertional malaise, they typically suffer an even greater intensity and/or length of symptoms afterwards. Studies suggest that metabolic, mitochondrial, immuno-inflammatory, and neurologic dysregulation and dysfunction play key roles in this debilitating symptom.^{17 - 19}

There is no cure for ME/CFS, so treatment focuses on symptom management. Approaches are tailored to an individual's symptoms and include activity management (pacing) to avoid postexertional malaise; addressing sleep disturbances, cognitive function, and orthostatic intolerance, which might involve a cardiologist or neurologist; supportive mental health and occupational counseling; and medications for pain, discomfort, sleep, and other symptoms.^{2 , 3 , 9 , 10 , 20 - 22} Treating ME/CFS comorbidities, including mast cell disorders and POTS, may help reduce the severity of symptoms.⁹ Complementary therapies, including meditation, relaxation therapy, dietary changes, and tai chi may also be used.^{1 , 2 , 9 , 20 , 21} The prognosis for ME/CFS varies. About 25% of people are so severely disabled that they are unable to get out of bed or leave their home and up to 75% are unable to work, while others may fully recover after 6 months to a year.^{2 , 6 , 9} The understanding and support from family and friends plays an essential role in helping people learn how to live with ME/CFS.²¹

Ongoing Research

Research efforts are focused on identifying the underlying causes of ME/CFS, especially the potential role of infection-associated mechanisms.²³ Additional studies are also needed to elucidate the pathophysiological mechanisms that underlie the illness. Many of these efforts are supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Allergy and Infectious Diseases (NIAID). Researchers are also exploring strategies for identifying reliable and specific biomarkers to help health care providers diagnose ME/CFS and monitor disease progression.^{5 , 10} Continued research aims to identify the genetic variations that are associated with ME/CFS, classify distinct ME/CFS subtypes, examine associations between gynecologic risk factors and ME/CFS, and develop targeted therapies for this complex, debilitating illness.^{5 , 10 , 14}

NIH supports a broad range of initiatives that are aimed at advancing our understanding of ME/CFS, including its causes, pathophysiology, and potential treatments.²⁴ For example, in a 2023 NIH-funded study, a research team led by NIH scientists identified a protein called WASF3 that is a potential contributor to the exercise intolerance and postexertional malaise that is seen in people with ME/CFS. The researchers determined that elevated WASF3 levels impaired mitochondrial energy production in muscle cells and that blocking the protein restored normal function. In addition, they found higher levels of WASF3 in muscle tissue samples from people with ME/CFS than in healthy individuals, suggesting a possible biological mechanism and therapeutic target for the condition.²⁵