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What Causes Chronic Fatigue Syndrome?

What We Know About What's Happening to You


Updated December 12, 2013

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

What Causes Chronic Fatigue Syndrome?

This is how the three glands of the HPA axis work together to produce cortisol.

Photo © HOPES, at Stanford

What causes chronic fatigue syndrome? Tough question! Despite lots of research, experts haven't been able to pin it on any single cause. Some believe chronic fatigue syndrome (ME/CFS) could result from multiple factors coming together under the right conditions. These factors may include:

  • Genetic factors
  • Central nervous system and hormone abnormalities
  • A virus or other infection
  • Immune system abnormalities
  • Stressful conditions
  • Exposure to toxins

Not everyone with ME/CFS has all of these factors going on. They likely have a combination of them that, for some reason, has led to the condition. Because different combinations of factors can cause different symptoms and changes in the body, experts are identifying categories or subgroups of ME/CFS. Eventually, subgrouping may help you and your doctor figure out the best way to treat you.

Genetic Factors and Chronic Fatigue Syndrome

Recent research links ME/CFS with genes involved in the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The HPA axis controls your sleep, response to stress, and depression.

In a 2006 study published in Pharmacogenetics, researchers looked at DNA that controls how your body reacts to trauma, injury and stress, and they found a common variation that could predict ME/CFS with 76% accuracy. The CDC called this "the first credible evidence of a biological basis for chronic fatigue syndrome." Still, researchers weren't able to pinpoint genetic markers or determine how variations influenced symptoms.

Other studies show genetic abnormalities in people with ME/CFS that influence immune function, cellular communication, and the ways your cells get energy.

All of this suggests that some people may be genetically predisposed to ME/CFS -- in other words, they're likely to get it if enough triggers come together. For example, if someone who's predisposed is going through a stressful time and is then exposed to a particular virus or toxin, they'll develop ME/CFS. Someone with a different genetic make-up, however, would come through the same scenario and be fine.

Central Nervous System and Hormone Abnormalities

As mentioned above, some people with ME/CFS have abnormalities in the HPA axis. Researchers are especially interested in some of the central-nervous-system chemicals and hormones controlled by the HPA axis:



  • Neurotransmitter changes
    Neurotransmitters are chemicals that communicate messages in your brain. Research has shown that some people with ME/CFS have abnormal levels of certain important neurotransmitters (serotonin and dopamine). Researchers are working to explain the role these abnormalities play in ME/CFS.
  • Stress hormone deficiencies
    Experts know levels of the stress hormone cortisol are low in ME/CFS patients, and they believe this could be what makes it hard to deal with stress -- either physical (such as infection or exertion) or mental. Cortisol replacement helps some, but not all, ME/CFS patients. In a 2008 study, women with ME/CFS had low morning cortisol levels while men with ME/CFS did not, which could help explain why the condition is far more common in women.
  • Disturbed circadian rhythms
    Your circadian clock (part of the HPA axis) regulates your sleep-wake cycle. Evidence suggests that in some people with ME/CFS this clock is thrown off, possibly by a mentally or physically stressful event, and the body isn't able to get the proper rhythm reestablished. People with this problem appear to spend more time in the rapid-eye movement (REM) phase of sleep, which is when you're dreaming. People in this subgroup of ME/CFS get more help from sleep medications than people in other subgroups, according to experts.


Many of the signs and symptoms of ME/CFS are similar to those of a lingering viral illness, so a lot of research has focused on the possibility of a viral or infectious cause. Researchers have examined three infection-related theories, though none has been proven:
  1. A virus or bacteria infects the body and damages the immune system. The damage then continues to cause flu-like symptoms even after the virus or bacteria is gone.
  2. After an infection, an abnormal action by the immune system triggers a virus that had become inactive to reactivate.
  3. A physiological response to viral infections occurs in people who are susceptible.

While not everyone with ME/CFS shows signs of infection, many do. Several pieces of evidence support a theory that some ME/CFS is caused at least in part by a virus:






  • Enterovirus connection
    In a 2007 study, people with ME/CFS were four times more likely than healthy people to have evidence of enteroviruses in their stomach tissues. Enteroviruses cause stomach infections, and symptoms of ME/CFS frequently start after that kind of illness.
  • Rnase L
    Your body uses the enzyme Rnase L to kill viruses that are attacking your cells, and ME/CFS patients frequently have high Rnase L activity.
  • Natural Killer (NK) Cells and T Cells
    NK & T cells in your immune system attack virus-infected cells, and people with ME/CFS frequently have impaired NK and T cell functions and numbers, suggesting chronic immune activity may be exhausting and depleting them.
  • Antibodies
    People with ME/CFS typically have high levels of antibodies to many infection-causing organisms that cause fatigue and other ME/CFS symptoms. These organisms include those that cause candida (yeast), human herpesvirus type 6 (HHV-6), measles, parvovirus and Epstein-Barr. Researchers have not been able to show that any of these is a significant cause of ME/CFS.
  • Post-illness onset
    Up to 80% of ME/CFS cases start suddenly after a flu-like condition.
  • Cluster outbreaks
    While the CDC has not confirmed most cluster outbreaks, reports of multiple people in the same household, workplace and community developing ME/CFS at the same time are not unheard of.

Some researchers suggest that changes in normally harmless bacteria in the intestine may play a role in the development of ME/CFS.

However, some evidence seems to run counter to the viral-cause theory. ME/CFS doesn't appear to spread through direct content, people with it don't appear contagious, and -- in spite of well-designed studies -- researchers have not been able to link ME/CFS with any specific infections.

On Page 2: XMRV, Immune System Abnormalities, Stressful Conditions, Chemicals and Toxins
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  3. Fibromyalgia & Chronic Fatigue
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  5. Causes & Risk Factors
  6. What Causes Chronic Fatigue Syndrome?

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