Background - Researchers have for several decades been concerned that the prolonged production of adrenal stress hormones - the glucocorticoids – could damage the brain and disrupt immune and sympathetic nervous system functioning. This paradigm of stress related disease has been almost entirely focused on increased not decreased cortisol production. Multiple studies have indicated that major depression is associated with high cortisol levels.

Studies in the last ten years or so, however, have indicated that a different kind of stress disorder – one characterized not by over but by under activity of the HPA axis – may be of equal concern. Hypocortisolism has been found in CFS, FMS, chronic pelvic pain syndrome, post traumatic stress syndrome (PTSD), rheumatoid arthritis (RA), asthma and allergies. Studies finding that people with these diseases report higher than normal rates of major stressors prior to their becoming ill have suggested an altered stress response may be implicated in their illness. Several researchers now posit that hypocortisolism may underlie the pathology in a wide range of diseases characterized by increased autoimmunity, inflammation, pain, fatigue, asthma or allergies. A 1994 study indicated that patients with genetically derived resistance to glucocorticoids often developed symptoms similar to those found in CFS and FMS. Glucocorticoid resistance or the impaired responsiveness to glucocorticoids do not appear to be the same as hypocortisolism but can for the purposes of this paper be considered synonymous with it; both result in impaired glucocorticoid activity.

While hypocortisolism has been linked with increased stress it is not, however, necessarily tied to disease. At least five studies have found hypocortisolism in healthy individuals who were under chronic stress.

Setting the Stage - Producing Cortisol - How is cortisol produced? The cortisol production pathway is given below

• a physical or psychological stressor prompts the release of corticocotropin releasing hormone (CRH) from the hypothalamus
• CRH and arginine vasopressin trigger the production of adrenocorticotropic hormone (ACTH) from the pituitary.
• ACTH causes the adrenal glands to release cortisol
• To Review - CRH (hypothalamus) + ACTH (pituitary) = cortisol (adrenal glands).

Hypocortisolism and CFS: the Evidence  With 23 studies on it and counting cortisol is certainly the most well studied substance in CFS. The evidence for hypocortisolism in CFS is, however, hardly overwhelming. Of the 23 studies done since 1991 that have measured urinary, salivary or plasma cortisol levels only just over 50% (n=12) have found low cortisol levels. The evidence for low ACTH  - the second stage in the cortisol production pathway - is even poorer; only 3/8 studies found low ACTH levels in CFS.

Basal cortisol and ACTH levels only tell part of the story, however. A more important question concerns how well the pituitary (ACTH) and adrenal glands (cortisol) respond to stress. CFS patients could have normal resting hormone levels and still have low hormone levels under stress; an underactive stress response could then cause them problems in dealing with stressors such as exercise, psychological stress, infection, etc. 

The evidence for a hypoactive stress response in CFS is fairly strong; 2/3rds of studies (8/12) have found a reduced ACTH response to stress. Since, as noted above, ACTH production by the pituitary triggers cortisol production by the adrenal glands, a reduced ACTH response could result in reduced cortisol production during the stress of infection, exercise, etc. Of the five studies that examined the cortisol response to stress, however, only two, found an impaired cortisol response.

Producing a Hypercortisolic State – What could cause a hypocortisolic state in CFS? Raison and Miller state there are at least six ways to reduce the effectiveness of glucocorticoids in the body. Some of the them entail reducing cortisol levels, others simply impair the effectiveness of cortisol when it is present. Either way all result in lowered cortisol activity. They are:

• Reduced production of the hormonal triggers needed for cortisol production (CRH/ACTH)
• A defect in adrenal gland production or release
• Defective binding proteins for cortisol that reduce cortisol availability to the cell
• A problem in the enzymes that metabolize glucocorticoids once they are in the cell
• A defect in the (multidrug) pump that pumps cortisol out of the cell
• Altered receptor levels or responsiveness

Is there evidence for any of these in CFS? There is some evidence for reduced CRH/ACTH production/responsiveness in CFS. There is also evidence of reduced adrenal gland productivity. Torpy found a trend towards increased frequency in CFS patients of a mutation in the cortisol binding globulin gene (CBG). Since CBG delivers cortisol to the cell then impaired CBG functioning would exacerbate any cortisol deficiencies already present (Torpy et. al. 2001). Torpy's study of a family with these mutations found they bore some similarities to CFS; they were often obese, they had low systolic and diastolic blood pressures and experienced overwhelming fatigue and moderate joint pain. They did not, however, display any of the flu symptoms often associated with CFS. Several family members did, however, met the CDC criteria for CFS and one did for FMS. Overall most studies suggest the HPA axis in CFS is under-responsive to stimuli.

Exacerbating An Already Bad Situation - Low hormone levels are usually counterbalanced by high levels of receptors for those hormones. Several studies indicate, however, that the opposite may be true in several diseases (chronic pelvic pain, FMS, RA and arthritis) associated with hypocortisolism  One study found that exposure to an allergen decreased the affinity cortisol receptors have for cortisol in allergy patients. Allergy is by definition an overactive immune response and cortisol is an important immune regulator. This study suggests that the allergic condition impairs the ability of the endocrine system to rein the immune system in.

But how could such a paradoxical situation develop? Why would receptor activity for cortisol fall instead of increase in the face of low cortisol levels. Why would the body exacerbate the cortisol deficiency already present? One intriguing answer given the immune activation sometimes seen in CFS involves increased levels of pro-inflammatory cytokines. Several studies have shown that increased levels of the IL-1a cytokine levels impair glucocorticoid receptor functioning. This suggests hypocortisolism could be exacerbated by as well as exacerbate a chronic infection. Thus the hypocortisolism in CFS could be caused by a chronic infection or contribute to the risk of a chronic infection or both (See below). It is not clear if this is happening in CFS but it illustrates the complex nature of the cortisol/immune reaction -an interaction that has barely begun to be explored in CFS. 

Hypercortisolism and Immune Activation – Infection is one of the many stressors that activate the stress response. Cortisol’s immunosuppressive effects include reducing lymphocyte functioning, macrophage activation, NK cell functioning, antigen presentation, T-cell proliferation and pro-inflammatory cytokine production. Cortisol's ability to inhibit phospholipase activity suggests reduced cortisol levels could also result in increased prostaglandin levels which would cause increased inflammation and pain. There is also evidence that hypocortisolism may result in reduced immune cell movement as well– a critical process in fighting infection.

The presence of hypocortisolism in an autoimmune disease, rheumatoid arthritis (RA), and two diseases associated with immune hyperresponsivity, asthma and allergy, supports the conjecture that low cortisol levels can lead to immune activation. More studies need to be done, however, to determine how important hypocortisolism is to the development and/or exacerbation of autoimmune and immune diseases.

Hypercortisolism is found in people with major depression. Not surprisingly given their high cortisol levels, depressed people usually exhibit reduced responsiveness to glucocorticoids. (As noted earlier the body commonly compensates for high levels of a substance by reducing its quickly it responds to it). This reduced responsiveness extends, interestingly enough, to the immune system. Poor glucocorticoid regulation of the immune system is believed to be responsible for the increased levels of inflammatory markers (Il-1, Il-6, TNF-a) often found in patients with major depression.

Raison and Miller suggest that, at least with regard to the immune system, that the hypocortisolism seen in CFS is a mirror image to the hypercortisolism seen in depression – both  result in increased inflammation; one through reduced responsiveness to glucocorticoids (depression), and one through reduced levels of glucocorticoids (CFS). In either case the ability of the stress response system to contain the immune response has been impaired.  This should result in increased levels of the main immune system mediators - the cytokines. It has long been intriguing that many symptoms in CFS are similar to those found in conditions with high cytokine levels. The state called ‘sickness behavior’ - which most of us go through when we catch a cold - characterized by fever, malaise, fatigue, poor concentration, etc., is believed to be caused by high cytokine levels in the brain. (This 'behavioral response' is believed triggered by the brain in order to cause the ill patient to slow down and conserve their energy for fighting off the pathogen.)  An inability to rein in the immune system because of a hypocortisolic state could result in increased cytokine levels and a prolonged state of 'sickness behavior' in CFS.

Not only can glucocorticoids inhibit the immune response but cytokines can, by impairing glucocorticoid receptor number and activity, impair the glucocorticoid response. This suggests the following feed forward mechanism could exist in a hypocortisolic state; low cortisol levels could lead to an inflammatory cascade that further impairs cortisol production which in turn leads to further cytokine production, etc.

This theory predicts that the hypocortisolic state in CFS should result in immune system activation. But are the immune systems of CFS patients activated? Much of the evidence is mixed; pro-inflammatory cytokine levels are sometimes increased in studies of CFS patients and sometimes not. A more compelling argument for immune activation in CFS may come from a recent study showing that impaired natural killer cell and T-cell activity in CFS is probably due to immune cell ‘burn out’ from over-activation.  Further evidence of immune activation comes from the gene expression studies in the form of increased numbers of immune genes, and increased rates of RNase L fragmentation and allergy in CFS.

Evidence For An Impaired Cortisol/Immune Interface in CFS - Only one study has started to examine whether the hypercortisolic state in CFS is synonymous with immune activation in CFS.  This study found that the ability of glucocorticoids such as cortisol to regulate immune activity was impaired in CFS. This is opposite to what was expected; the researchers thought, given the low levels of cortisol usually found in CFS, that the immune cells in CFS patients would have been hyper-responsive to it; as we noted earlier the body usually compensates for a deficiency in a substance by increasing its responsiveness to it. The opposite appears to have happened in CFS; this would, of course, exacerbate the effects the low cortisol levels might have on immune regulation in CFS.

Hypocortisolism and Sympathetic Nervous System (SNS) Activation – Since cortisol also restrains the production, turnover and release of the catecholamines (norepinephrine/epinephrine) that regulate SNS activity, a hypocortisolic state could lead to increased SNS activity. Several studies have found evidence of increased SNS activity in CFS. 

Hypocortisolism - A Protective Mechanism? Could the hypocortisolism found in CFS be protective? Dr Cheney has long postulated the fatigue present in CFS is more a protective than pathologic feature.

The idea that the body can produce symptoms or ‘behaviors’ during illness that compel an individual to save their energy for healing is not new. As noted above the symptoms produced during the acute stages of infectious disease called ‘sickness behavior’ such as malaise, fever, poor concentration, sleepiness are believed to be produced by cytokines. In a similar sense the pain produced during trauma is designed to limit the use of wounded limb.

Raison and Miller suggest that hypocortisolism could be an adaptive response to certain types of chronic stress. We know the stress response plays a key role in ramping down the production of pro-inflammatory cytokines during the later parts of an infection. But what if the infection has not been resolved by the time the immune system inhibition has occurred? Wouldn’t immune system down regulation be injurious at that point? Raison and Miller ask which is worse - an ongoing infection or an impaired stress response, and come down squarely on the side of an ongoing infection. They suggest that the body could lower its production of glucocorticoids in order to allow the immune system to ramp up again.

Several CFS researchers have suggested a process like this could be occurring in CFS. In 2003 Van Hoof, Cluydts and De Meirleir posited that the atypical depression (fatigue, malaise, aching muscles, etc.) often seen in CFS is not due to an affective (mental) disorder but is an adaptive course the body has taken to save it’s resources for battling a chronic infection. They note that the administration of the pro-inflammatory cytokine Il-1 has been shown to produce long term changes in HPA axis activity in laboratory animals. Similarly depression and fatigue often follow the administration of the cytokine interferon as well.

The idea that the hypocortisolism found in CFS is an adaptive or protective response is interesting given a study indicating that elderly subjects with hypocortisolism had lower levels of allostatic load than elderly subjects with normal cortisol levels. Since aging is synonymous with stress this study suggests that hypocortisolic state may be advantageous during periods of chronic stress. This scenario suggests that without the hypocortisolism present in CFS, CFS patients would have higher allostatic loads than they do.

The consequences of chronic immune activation that might result from this can be severe, however, and include an increased risk of autoimmune diseases and increased cell death in the central nervous system (CNS). The pro-inflammatory cytokine TNF-a released during chronic immune activation is neurotoxic to cells in an area of the brain (hippocampus) involved in regulating the stress response. Rodents treated with an anti-glucocorticoid agent designed to put them into a hypocortisolic state demonstrated increased TNF-a associated neurodegeneration.

Conclusions – It is impossible at this point to know how important hypocortisolism is in CFS. While it seems clear that hypocortisolism is often present in CFS it is unclear whether it is simply a product of the chronic stress present in CFS or if it is a central factor in CFS pathophysiology. Some recent studies have suggested the former is more likely to be true. A finding that reduced cortisol levels are correlated with disease duration suggest it is a function of chronic stress that builds over time. A prospective study that did not find altered HPA axis functioning in EBV patients with long term fatigue suggested the same. A study that temporarily resolved the hypocortisolic state in CFS through the use of hydrocortisone which found some benefits but that in no way resulted in the resolution of CFS suggested that hypocortisolism is a secondary not primary factor in CFS.