The causes of chronic fatigue syndrome (ME/CFS) are unclear. Despite extensive research, experts haven't been able to pin the disease on any one factor, and some believe the condition could result from multiple factors coming together under the right conditions. These factors may include:

Genetic predisposition

A virus or other infection

Immune system abnormalities

Stressful conditions

Central nervous system (CNS) and hormone abnormalities

Exposure to toxins

Not everyone with chronic fatigue syndrome has all of these factors. They likely have a combination of them that, for some reason, has led to the condition, which is more common in women than men.﻿﻿

© Verywell, 2018

Genetics

People may be genetically predisposed to ME/CFS—in other words, they're likely to get it if enough triggers come together.﻿﻿ For example, someone who's predisposed and is going through a stressful time and is then exposed to a particular toxin may develop ME/CFS, while someone in the same scenario but with a different genetic makeup would not.

The Centers for Disease Control and Prevention (CDC) notes that there are suggestions that chronic fatigue syndrome is influenced by both genes and the environment because some members of the same family have the condition, but it isn't clearly inherited.

Research is trying to identify the genes that could be responsible. Some has focused on the 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. There may be genetic abnormalities in people with ME/CFS that influence immune function, cellular communication, and the ways your cells get energy.

Infections

Many of the signs and symptoms of chronic fatigue syndrome are similar to those of a lingering viral illness, so research has focused on the possibility of a viral or infectious cause. An infectious trigger is also suspected because many ME/CFS cases start suddenly after a flu-like condition.﻿﻿

The CDC notes that about 10 percent of people who have had an infection with Epstein-Barr virus (the usual cause of mononucleosis), Ross River virus (spread by mosquitoes in Australia and New Guinea), or Coxiella burnetti (the cause of Q fever) go on to develop symptoms that meet the criteria for ME/CFS.

Each of these viruses often shows few symptoms in humans, but those who have more severe symptoms are more likely to develop chronic fatigue syndrome symptoms.

Other infections that have been suspected and studied include HHV-6, Lyme disease, and enterovirus. However, none of these infections has been shown to cause ME/CFS.﻿﻿

Researchers have examined three infection-related theories, though none has been proven:

An infection damages the immune system. The damage then continues to cause flu-like symptoms even after the virus or bacteria is gone.

After an infection, an abnormal action by the immune system triggers a previously dormant virus to reactivate.

A physiological response to viral infections occurs in people who are susceptible.

People with ME/CFS may have higher levels of antibodies to some infection-causing organisms and show signs of chronic immune system activity, suggesting the body is fighting an infection. Some researchers even theorize that changes in normally harmless bacteria in the intestine may play a role in the development of chronic fatigue syndrome.﻿﻿

However, some evidence seems to run counter to the viral cause theory. ME/CFS doesn't appear to spread through direct contact, people with it don't seem to be contagious, and—in spite of well-designed studies—researchers have not been able to link chronic fatigue syndrome with any specific infections. For example, there was a great deal of excitement over a study finding a newly discovered retrovirus, XMRV, in ME/CFS patients. However, later studies did not confirm the results; it could be that the original study was flawed due to contamination of the samples.

Immune System

Chronic fatigue syndrome appears to have some features in common with autoimmune diseases such as lupus or multiple sclerosis, in which the immune system mistakenly attacks healthy parts of the body. One theory is that allergies, stress, and infection may combine to deplete a chemical called adenosine triphosphate (ATP), which stores energy in cells. Some ME/CFS patients show evidence of decreased ATP production.﻿﻿

Irregularities may be seen in the immune systems of people with chronic fatigue syndrome, but researchers have not found a consistent pattern of abnormalities. Among the most common are allergies and an overactive immune system.

The immune system produces many chemicals that are collectively called cytokines. These act on immune cells to regulate their behavior in many ways. Some ME/CFS patients have high levels of these chemicals, which scientists theorize could cause symptoms of chronic fatigue, including exhaustion and muscle aches.﻿﻿

Changes can also be seen in the function of a couple of types of immune cells in people with ME/CFS. T-cells are active in both producing and calming the immune response. Some people with this syndrome show abnormal T-cell activation, while others do not.﻿﻿ Natural killer (NK) cells are immune system cells that help the body fight infection. Low-functioning NK cells are seen in people with chronic fatigue syndrome, and it appears that the worse the functioning of these cells, the more severe the illness.﻿﻿ Research is ongoing to find the specific mechanism that could lead to impairment of these cells.

Hormones and the CNS

Researchers are especially interested in some of the central nervous system (CNS) chemicals and hormones controlled by the HPA axis. These may be influenced by genetics, infection, or stress.

Neurotransmitter Changes

Neurotransmitters are chemicals that communicate messages between nerve cells in your brain and throughout your body. Each bodily function, thought, and emotion is linked to the operations of specific neurotransmitters. When the activity of a particular one is too high or too low, things can start to malfunction. Some people with ME/CFS have abnormal levels of certain important neurotransmitters (serotonin and dopamine).﻿﻿ It could also be that there is enough present but the receptors for them are not working properly. Researchers are working to explain the role these abnormalities play in chronic fatigue syndrome.

Stress Hormone Deficiencies

The level of the stress hormone cortisol tends to be low in ME/CFS patients. Some theorize this could make it hard to deal with stress, either physical (such as infection or exertion) or mental.﻿﻿ Cortisol levels are not diagnostic for the condition and replacement helps some, but not all, chronic fatigue patients.

Disturbed Circadian Rhythms

Your circadian clock (part of the HPA axis) regulates your sleep-wake cycle. This clock could be thrown off by a mentally or physically stressful event and the body may not get the proper rhythm reestablished, resulting in the sleep disturbances seen in ME/CFS. Some people with the condition have either reduced or extended periods of the rapid-eye-movement (REM) phase of sleep,﻿﻿ which is when you're dreaming.

Psychological Factors

Researchers believe your psychological makeup, personality, and social situation can impact whether you'll develop ME/CFS, but they don't yet fully understand the complex relationship between these factors. While they are probably not primary causes of chronic fatigue syndrome, they're likely to play a role in making you susceptible.

Note that ME/CFS is not considered a primarily psychological illness, nor does having it mean someone is psychologically "weak" or unable to cope with things. While it is sometimes linked to clinical depression,﻿﻿ chronic fatigue syndrome is a distinct condition.

Chemicals/Toxins

In some, chronic fatigue and pain are associated with exposure to various chemicals and environmental toxins. These can include solvents, pesticides, or heavy metals.﻿﻿ However, because most people have been exposed to these types of chemicals at some point, it's difficult to track down which ones might be causing problems.

A condition called multiple chemical sensitivity (MCS) causes many of the same symptoms as ME/CFS, and the two are believed to be overlapping conditions.

Your Sex

Two to four times as many women are diagnosed with ME/CFS as are men.﻿﻿ Any cause, if discovered, would need to account for this difference. There are sexual differences in hormones, brain chemistry, immune system function, inflammation, and genetics:

Women have less testosterone, which plays a role in preventing muscle fatigue.

There are sex-based differences in the stress hormone cortisol and the neurotransmitter serotonin.

Pre-menstrual syndrome is a common overlapping condition with ME/CFS and often aggravates symptoms. ﻿ ﻿

﻿ A genetic predisposition for ME/CFS could be significantly influenced by the difference in male and female chromosomes and gene expression.

There could also be a bias in diagnosis. Men might not seek medical attention for their symptoms due to perceived social pressure to "tough things out," among other reasons. Doctors may also have a bias that ME/CFS is a female disease and be less likely to consider the diagnosis for men with the symptoms.

As research continues, there may be a breakthrough in identifying the cause and risk factors for ME/CFS. In the meantime, if you feel your symptoms align with chronic fatigue syndrome, advocate for yourself and work with your doctor to get to the bottom of them.