Even in the absence of disease, there are differences between males and females in the way their bodies work – physiological differences. These are hugely important in explaining the variations in susceptibility to disease, and the disparity in response to medication and treatment.
For example, a recent paper summarises that the sex hormones, oestrogen and testosterone, have different impacts on immune responses which mean that:
- Males
- More susceptible to infections from outside the body.
- More resistant to the development of autoimmunity and abnormal cell growth.
- Females
- Higher susceptibility to pathogens that can establish persistent infections inside the cells of the body, autoimmunity and abnormal cell growth.
- Reduced susceptibility to infections from outside the body.
Other studies have suggested that there may also be differences between men and women in how the autonomic nervous system (ANS) works – the ANS is responsible for controlling processes in the body that occur without our conscious control, such as our heart rate.
The ANS includes:
- The parasympathetic nervous system – responsible for the “rest and digest” response which includes actions such as constricting pupils, increasing digestion, slowing heart rate, and sleep.
- The sympathetic nervous system – responsible for the “fight and flight” response which includes actions such as dilating pupils, decreasing digestion, increasing heart rate, and alertness.
Research has shown that men may have higher activity of the sympathetic nervous system, while women have higher activity of the parasympathetic nervous system.
As the ANS, the immune system, and persistent infections – such as latent viral infections – have been linked with ME/CFS, these differences in susceptibility may play a role in explaining the variations in the numbers of men and women with the disease.
Differences in age of onset
Findings suggest that men tend to develop ME/CFS earlier in life than women – or, where onset has been similar between men and women, there has been a tendency for women to develop the disease later in life. This may be explained, at least partially, through differences in periods of significant hormonal change, and how these relate to the observed age of onset of ME/CFS for both males and females.
For males, age of onset has been found to be most common between 10 and 19 years of age, which includes puberty. For women, age of onset has two peaks; one, as in males, between 10 and 19 years, but another occurring at ages 30 to 39, which often includes pregnancy and postpartum period.
Not only do these age ranges include periods of significant hormonal change, but they also may correspond with times of increased susceptibility to infection, which in turn increases the risk of developing ME/CFS either at the time, or in the future. Despite the observation that onset of ME/CFS seems to be linked to periods of hormonal change, in a recent review, Thomas and colleagues reflect that there has been little research which directly considers the biological mechanisms involved, or the involvement of specific hormonal related events and medications in ME/CFS.
Differences in symptoms
There is conflicting evidence relating to whether there are differences in symptoms experienced by men and women with ME/CFS.
One small study, published in 1999 (behind a paywall), compared the experiences of 18 men and 59 women with “CFS” and found that there may be no difference in the symptoms experienced between men and women with “CFS” – the three most common symptoms for both men and women were extreme fatigue, muscle pain and cognitive problems.
However, in studies with larger sample sizes, men with ME/CFS appear to report lower levels of certain symptoms compared with women. For example, ME Research UK has previously written about a study that investigated differences in symptoms between 119 males and 1190 females with ME/CFS – here males reported lower levels of symptoms such as morning stiffness, pain, dizziness, and sexual dysfunction compared with women. More recently, early findings from the DecodeME study (14,257 female and 2,817 male participants) have also indicated that males who participated in the study reported fewer symptoms. Considering the findings from studies exploring the lived experiences of men with ME/CFS, or a diagnosis of “CFS” – and from men with other illnesses more common in women than men such as rheumatoid arthritis, breast cancer and fibromyalgia – it is possible that these differences may, at least in part, be explained by societal pressure to appear masculine, which may mean that men with ME/CFS delay seeking medical advice or “battle through” symptoms, downplaying severity.
In addition, while it is worth remembering that the findings from DecodeME are not final, and participant recruitment was ongoing at the time of publication, the number of male respondents in this DecodeME publication may not be completely representative of the number of men with ME/CFS in the UK. If taking a ratio of 1:3 or 1:4 we would have expected somewhere between 3,415 to 4,268 male participants, while in the DecodeME study 2,817 participants were male. Furthermore, only 12.7% of participants had severe or very severe ME/CFS, which again does not fully capture the reality which is nearer 25% of all people with the illness. This potentially means that men with more severe symptoms are not reflected in the analysis either.
Differences in the response to exercise
A further study, reported by ME Research UK, considered how 24 female and 11 male participants with ME/CFS (diagnosed using either the Canadian Consensus Criteria or Fukuda criteria for ME/CFS and CFS, respectively), and 21 female and 14 male healthy controls responded to an exercise test which was designed to trigger post-exertional malaise (PEM). This study looked at markers in the blood related to immune function before exercise, at maximum effort, and four hours after maximum effort. While the results of the study were complex, they showed a difference between males and females in the way genes relating to immune function are expressed both at maximum physical exertion and four hours after. Although these results suggested that males and females may respond differently to exercise in the short term, this study did not consider the longer term effects.
Another study, published in 2023, considered how 37 participants, who met the Fukuda criteria for CFS (22 female and 15 male), and 144 controls (141 female and 3 male) responded to a different exercise test, and this time the participants were followed up for a longer period of time:
- On days 1 to 7, participants were asked to complete questionnaires relating to levels of fatigue and their physical limitations.
- On days 8 and 9, the exercise test was carried out – this included 30 seconds of squats, followed by a 6-minute walking test.
- Days 10 to 15 involved the participants completing a daily web diary in which they were asked to record on a scale of 1 to 10 their fatigue levels and how this affected work, housekeeping and exercise.
- Across days 1 to 15, all participants wore heart rate monitors.
Overall, levels of fatigue reported were slightly lower for men compared with women – something the researchers suggested may be due to differences in the disease itself, for example in how symptoms present, or in how males experience symptoms of the disease – which again links to how some men with ME/CFS may feel pressure to appear masculine and downplay symptoms.
Male and female participants with ME/CFS were able to do similar amounts of activity during the exercise test, and in response to the test there was little difference between males and females in the rate of recovery; at day 15, both male and female participants had recovered to the fatigue score they reported on day 1. Interestingly, in the last two days of tracking, heart rate for the male participants significantly decreased – something that was not observed for females in this study.
While this study did consider PEM over a longer period of time, it is possible that a more intensive exercise test than the one used may be required to better detect differences between males and females with ME/CFS – in addition to studies with larger numbers of participants.
Differences in autonomic function
There is also some research which considers differences in function of the autonomic nervous system between men and women with ME/CFS. A study published in 2021 investigated heart rate variability (HRV) – a marker of autonomic function – in 32 men and 45 women who met the Fukuda criteria for CFS, and 19 male and 25 female controls who were matched for age. The researchers also asked participants about their symptoms including fatigue, autonomic dysfunction, sleep quality, and anxiety and depression.
This study found that for both male and female participants in this study, lower heart rate variability was found to be associated with greater physical severity of the ME/CFS.
Results also showed that compared with females, males with ME/CFS had:
- Different heart rate variability profiles – generally, men had higher HRV values (higher HRV measures are usually a marker of better health).
- Higher systolic blood pressure.
- Lower heart rate.
- Lower scores for questionnaires that measured self-reported:
- Symptoms of autonomic dysfunction.
- Frequency of both physical, and emotional symptoms. Symptoms assessed included; headaches, problems falling asleep, restlessness, concentration, and slowness of working.
- Levels of functional limitations due to fatigue.
- Sleep quality.
- Higher scores for a questionnaire that measured self-reported anxiety and depression.
The authors suggested that results indicate higher activation of the parasympathetic nervous system in women, but that women with ME/CFS may have reduced activation to a level similar to that of a healthy man. Exactly what this means – particularly for men – remains unclear.
Differences in the levels of fat molecules in the blood
One study that considered physiological differences between men and women with ME/CFS looked at fat molecules (lipids) which are important in both immune and inflammatory pathways in the body, and also in the function of cells which produce energy (mitochondria) – all of which have been implicated in ME/CFS.
This study considered levels of lipids in the blood in 50 people with ME/CFS (diagnosed using either the Fukuda, or Canadian Consensus Criteria for CFS and ME/CFS, respectively) and 50 healthy controls (25 males and 25 females in each). Findings suggested that there were differences in lipid levels between those with ME/CFS and healthy controls, and that these varied by sex. Results were complex but in summary:
- Male participants with ME/CFS had increased levels of:
- A lipid thought to be involved in immune response (hexosylceramide; HexCer)
- Several lipids that may be linked to inflammation and susceptibility to autoimmune and chronic inflammatory diseases (LA-derived oxylipins)
- Female participants with ME/CFS had decreased levels of:
- A particular lipid involved in regulation of inflammatory pathways (phosphatidylethanolamine; PE)
- HexCer
For both male and female participants, lipid levels were also found to be associated with self-reported symptoms of ME/CFS.
This study was carried out in a relatively small number of people, and although suggestive that there may be differences in lipid profiles for males and females with ME/CFS, more research is needed, both to explore what these differences are with larger groups of people, and to better understand exactly the roles these lipids play in ME/CFS.
Summary
There is very limited evidence related to the physiological differences between men and women with ME/CFS. This means that no conclusions can be drawn and, currently, we do not know enough about the ways in which men and women with ME/CFS are different.
The studies summarised here suggest that there may be differences between men and women with ME/CFS relating to:
- Onset of disease – possibly earlier in men.
- Symptoms experienced – although findings conflicting men may experience lower levels of symptoms.
- Heart rate variability (a marker of autonomic function) – men had better scores and this is generally seen as a marker of better health.
- Levels of anxiety and depression – observed to be higher in men.
- Response to exercise in the short term – relating to gene expression and immune function; the exact genes affected were different for men and women.
- Response to exercise in the longer term – results were complex. Although little difference was seen in the time taken to recover to baseline levels of fatigue, men with ME/CFS experienced a drop in heart rate that was not seen in women.
- Differences in lipid profiles – which are important in both immune and inflammatory pathways, for males and females with ME/CFS.
Despite these findings, it is important to note that the relatively small number of participants used in each study (with the exception of DecodeME), and the lack of replication of findings across different populations, means that much more research is needed to better understand exactly what the differences between men and women with ME/CFS are, and what these differences mean for diagnosis and treatment.
Takeaway messages
- Even in the absence of disease, there are differences between males and females in the way their bodies work – physiological differences – and these are related to variations in susceptibility to disease.
- Little is known about the physiological differences in men and women with ME/CFS.
- The little research that does exist suggests that that there may be differences between men and women with ME/CFS for example in autonomic function and response to exercise – despite this there is not enough research to draw any firm conclusions.
- Much more research is needed to better understand exactly what the differences between men and women with ME/CFS are, and what these differences mean for diagnosis and treatment.
