“The HPA axis [is] a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality and energy storage and expenditure.” Wikipedia


Is the HPA axis coming back? Broderick’s model suggests so.

The HPA axis and low cortisol readings were a big deal for many years in chronic fatigue syndrome research, but interest has faded of late.  A recent meta-analysis concluded that the cortisol awakening response that occurs early in the day is associated with fatigue in ME/CFS (while total cortisol and other measures are not.)

The HPA axis may be making a re-appearance, though. We recently saw that it may be implicated in exercise intolerance in autoimmune disorders and fibromyalgia, and this study suggests that HPA axis problems, in combination with other systems, may play a key role in perpetuating chronic fatigue syndrome.

“The hypothalamic-pituitary-adrenal (HPA) axis, a key component in the body’s stress response, serves to articulate changes in a broad range of homeostatic regulators as a function of environmental cues. Such cues can consist of both physical stressors (injury, infection, thermal exposure) and psycho-emotional stressors (frustration, fear, fight or flight decisions).”  Authors

The authors noted that the effects the HPA axis has on energy production and sympathetic nervous system and immune system functioning cause HPA axis problems to show up in a wide variety of disorders including chronic fatigue syndrome, depression, PTSD. Alzheimer’s, GWI, and others.

It’s a major, major system.

PLoS One. 2014 Jan 8;9(1):e84839. doi: 10.1371/journal.pone.0084839. eCollection 2014. A role for homeostatic drive in the perpetuation of complex chronic illness: gulf war illness andchronic fatigue syndrome. Craddock TJ1, Fritsch P2, Rice MA Jr3, Del Rosario RM3, Miller DB4, Fletcher MA5, Klimas NG6, Broderick G7.

‘Backup Programs’ Take Over

Broderick has been describing both chronic fatigue syndrome and Gulf War Syndrome as disorders characterized by stable but suboptimal homeostatic ‘states’.  This suggests that the bodies response to whatever triggered ME/CFS  (infection?) or GWS (toxins?) was to lock it in  a new suboptimal physiological state.

feed-forward process

If not contained feed-forward processes can quickly run out of control. Broderick believes poorly controlled feed-forward processes have pushed people with ME/CFS into suboptimal operating states

Broderick and Craddock believe the body has ‘backup programs’ that get activated during times of crisis. In the case of ME/CFS and GWS and some other chronic illnesses, he believes those backup programs are still running.

These alternate stable regulatory regimes occur due to the feed-forward and feedback mechanisms within the system and may allow escape routes for survival of an insult and provide support in the medium or long-term to what is equivalent to an uneasy cease-fire or adaptive compromise. – Authors

“Feed-forward’ or positive feedback processes play a key role in the model. Feed-forward processes are similar to getting interest on your money: as long as they’re in place they continue to build on each other.  They play important roles in allowing the body to quickly ramp up its defenses, but they should be controlled by feedback loops that damp them down and return the body to ‘homeostasis’.

Broderick’s models suggest that overly large feed-forward responses at the time of ‘stress’ (infection, wound, psychological stress) can break the system causing it not to return to homeostasis but to produce multiple other stable physiological states.  (The Dubbo study’s finding of high rates of pro-inflammatory cytokine production and more severe symptoms in people with an infection who developed ME/CFS is suggestive of a large feed-forward process involving the immune system.)  One positive feedback loop incorporating HPA receptors, for instance, resulted in a permanent state of low cortisol production.

Modeling Chronic Fatigue Syndrome

“We found numerous stable resting states that differ significantly from normal and were indicative of complex and persistent regulatory imbalances.”

Brockerick uses molecular and cellular data from the HPA, HPG (hypogonadal) and immune systems to build a model (run thousands of times)  that he believes helps to explain why people with ME/CFS are seemingly locked into their state of poor health.

His inclusion of male and female hormone data offers insights into a part of our physiology that is clearly involved in ME/CFS but is rarely assessed. Studies indicate high rates of gynecological disorders are present in women with ME/CFS. One researcher told me that the complexity of the female hormonal system and confounding factors such as high rates of birth control in our society make it difficult to assess the role the hormonal system plays in this disorder. (Poor funding undoubtedly plays a role as well.)

Broderick’s models suggest, however, that interactions between the hormones and the immune system could play a key role in maintaining the low cortisol present in this disorder and help explain why more women than men come down with it.

Hormone System Protects Men/Puts Women at Risk for ME/CFS

man and woman

Broderick’s model suggests women’s hormonal system’s put them more at risk of ME/CFS

It turns out that the male hypogonadal axis protects men from having low cortisol.  (In fact, the model, as it exists now, suggests men should never enter into a steady state of low cortisol.)  High estrogen levels, on the other hand, were able to push women into a low cortisol state during some types of HPA axis activity.  (If I understand this correctly, the high estrogen is not the problem; the problem lies in a feed-forward process involving glucocorticoid receptors.)

The immune system both regulates and is regulated by the HPA axis. Cytokines produced by the innate immune system (which is activated in ME/CFS) and by T-cells activate the HPA axis.  Cortisol, on the other hand, reduces innate immune system activity and inflammation. (The low cortisol found in ME/CFS may therefore lead to inflammation.)

Female Dominance and Gynecological Issues in ME/CFS Support the Model

female with puzzle pieces on face

The female dominance in ME/CFS explained?

Some findings support the Craddock/Broderick model. The female dominance, the increased rates of ME/CFS in women from 40- 49, and the high rate of gynecological disorders in ME/CFS all suggest that Broderick’s model of female hormonal suppression of the HPA axis could play a role in ME/CFS. Altered hormone levels and increased cortisol especially during the third trimester of pregnancy could cause the symptom relief some women experience during the third trimester.

(Increased production of cortisol in pregnancy is usually associated with increased levels of cortisol-binding globulin (CBG) which binds to the extra cortisol leaving the normal levels of active cortisol in the blood.  Some ME/CFS studies, however, suggest that a genetic variant of CBG alters its ability to bind to cortisol in some patients.  Ironically, the women experiencing relief from symptoms in ME/CFS may be doing so because they have what’s thought to be a detrimental form on CBG.

Perpetuating Chronic Fatigue Syndrome – Not Causing It

Broderick doesn’t believe his model of female hormone-induced HPA axis suppression and immune dysregulation causes chronic fatigue syndrome, but he does believe it may help to perpetuate it. In stating that these physiological states may lay the foundation for a variety of pathological problems, Broderick clearly sees the potential for different versions of ME/CFS to emerge in different patients.

(We recently saw that low cortisol and immune issues may play a role in the reduced exercise tolerance found in two autoimmune disorders, rheumatoid arthritis, and lupus. Just as in chronic fatigue syndrome, autoimmune disorders are dominated by women.)

These stable states present a ‘regulatory barrier’ to change; i.e., they may make it more difficult for therapies that theoretically should help to actually have an effect.  Their existence suggests that multiple therapies targeting a variety of targets may be necessary to nudge the now stable system off-kilter allowing it to return to it’s ‘normal resting state’.  (Dr. Cheney has long suggested ME/CFS is a ‘protective state’ and used to note the push-pull phenomena he found in his patients; he would push them towards health and something would pull them back.)

A Different Model of Disease

Broderick’s model suggests that ME/CFS (and other chronic illnesses) are perpetuated not by the failure of one factor or the other, but by glitches in a series of coordinated responses that end up pushing the system into a ‘new normal’ state.  Even in seemingly closely associated disorders such as ME/CFS and GWS the new normal states can be very different.

cartoon of a push

Do the systems in ME/CFS simply need the right push to get them back on track and functioning normally?

While the multiple facets in Broderick’s models may seem a bit daunting from a treatment perspective, the models nevertheless provide considerable hope for people with ME/CFS.  They suggest that simply breaking the hold of the new ‘operating state’ may be enough to allow the system to return to normal; i.e., there may be no need for long and possibly damaging drug regimens. There’s simply the need for the right treatments to nudge the system far enough in the right direction for it to reset itself.

In conversation, he noted (if I got this right) that people with ME/CFS seem more ‘stuck’ in their suboptimal state than people with GWI, and it may take more to get them out of it.  Broderick’s data suggested that something, perhaps a pathogen, was forcing people with ME/CFS to remain in that state. People with GWI, on the other hand, had been pushed into a suboptimal state but nothing other than the fact that their bodies had accommodated to this state was holding them there.


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