There are several types of signaling molecules (hormones) in the body, including fat-soluble molecules, called steroid hormones.
Steroid hormones, such as those produced in the adrenal gland (cortisol and adrenaline), and sex hormones (like oestrogen and progesterone), play a key role in many processes in the body, including those which have been found to be dysregulated in people with ME/CFS:
- Metabolism (generation of energy from fats, proteins, and carbohydrates).
- Maintaining fluid balance and managing blood pressure.
- The immune response and inflammation.
Previous research has reported differences in steroid hormones between people with ME/CFS and healthy controls, studies have also identified that there may be differences in hormone levels between men and women with the disease. Despite this, no research had considered the complex network of relationships between steroid hormones – and whether this may look different for people with ME/CFS.
This gap in the research led a team of researchers from Australia and Sweden to carry out a small exploratory study investigating whether steroid hormones, and the links between them, differed between a group of 24 people with ME/CFS (who fulfilled the Canadian Consensus Criteria and the Institute of Medicine (now National Academy of Medicine) for ME/CFS, and the International Consensus Criteria for ME) and 24 age and sex matched controls.
Results showed that healthy controls had 52 significant associations between steroid hormones. However, people with ME/CFS only had one – the relationship between cortisol, the hormone which is involved in regulating stress and metabolism, and corticosterone which is not only associated with the stress response, helping to manage energy and immune function, but also contributes to the regulation of the sleep-wake cycle by promoting alertness during the day.
The research team suggested that for people with ME/CFS, this result indicated the potential breakdown in the complex communication process between hormones, and that this may underly key features of the disease including impaired stress tolerance, sleep disturbances, cognitive fog, and immune dysregulation. Interestingly in the paper, the authors highlight the overlap between these ME/CFS features, and those seen individuals with hormonal imbalances which can occur because of medical conditions like hypothyroidism, hyperthyroidism, diabetes, and Addison’s disease.
For people with ME/CFS results also indicated dysregulation of:
- The HPA axis, or hypothalamic-pituitary-adrenal axis – a complex set of interactions between the hypothalamus, pituitary gland, and adrenal glands. It plays a critical role in regulating stress responses, mood, digestion, immune function, and energy metabolism. The HPA axis is responsible for the production of the hormone cortisol.
- Progesterone signaling – progesterone is a sex hormone produced in both males and females. It is involved in the menstrual cycle and pregnancy, but is also crucial to metabolism, brain function, and the production of other steroid hormones such as corticosteroids which are produced in the adrenal glands. Notably, corticosteroids are involved in a wide range of processes in the body – including those which have been shown to be linked with ME/CFS disease mechanisms – such as the stress response, immune response, and the regulation of inflammation, carbohydrate metabolism, breakdown of protein molecules, and blood electrolyte levels.
Given the differences in rates of ME/CFS in men and women, and evidence suggesting ME/CFS symptoms may be associated with the menstrual cycle and reproductive phase, the finding relating to impaired progesterone signaling in people with ME/CFS is of particular interest. The research team emphasise that differences between male and female hormone profiles should be considered in ME/CFS research, and that accounting for sex differences in hormonal shifts throughout the life course may be key to understanding ME/CFS disease mechanisms.
The findings from the study clearly justify the need for further research investigating the role steroid hormones may play in ME/CFS disease mechanisms. However, several limitations of the study, acknowledged by the authors, mean the results must be interpreted with caution. One key limitation was that only a small number of participants took part. This means that the study may have lacked the statistical power needed to identify significant associations, and that the researchers were not able to consider whether there were differences in interactions between steroid hormones by factors such as ME/CFS severity – in another small study, steroid hormone levels were found to be different in women with severe ME/CFS compared with those who had mild ME/CFS.
As hormones have such wide reaching effects in the body, the research team recommended that an approach which considers the integrated effect of hormones across body systems – including the immune system, metabolism, and the nervous system – is required to enable scientists to identify potential panels of biomarkers for the ME/CFS which may not be apparent when considering individual systems in the body alone. In the paper it was also recommended that future work should include larger numbers of participants, study designs which follow participants up over time (longitudinal study designs), and consideration of the impact the menstrual cycle may have.
