“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.
‘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.
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
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
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.
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.
It’s still all guesswork isn’t it.
Keeping positive. Thumbs up for trying. It’s comforting to know there’s researchers out there moving mountains to obtain solutions for sufferers (including us men). Admirable. Now get them back to work so I can get back to work!!!!
ME appears to have similar triggers to cancer.
Cancer is not one disease. It can be triggered by viruses, toxins, bacteria, trauma, and hormones.
I think men are more out of touch with their bodies and more likely to accept a more tangible explanation for their failing health.
I think men are more likely to accept depression, obesity, alcohol, smoking, …..”You did this yourself” type diagnosis, and therefore are excluded from ME diagnosis by complicity with ill informed medical practitioners.
I think he got the part of what is keeping pple stuck in their sub optimal state wrong, it isn’t a virus but rather a total reconfiguration of the brain and HPA and how it responds to stress and fear. That prolonged exposure actually reshapes the brain and the parts that modulate stuck responses have been made smaller and work out of whack.
This is a very different model than one suggesting a virus… what is interesting is … has cfs/me/fms always been around and we are just noticing it more then due to more reporting of it?
Actually when I talked to Broderick last year he felt that a pathogen might be keeping the system in the ME/CFS patients more stuck than the system in the Gulf War Illness patients. I just didn’t get that in the blog.
I’m looking forward to reading this study, this all sounds pretty vague. If his theory involves systems within the body already there should be no problem accessing medications for treatment. Certainly we’ve seen enough studies to know that cortisone alone is not the answer.
Greg
believe it or not (and I know a lot of people think its nonsense) this to me sounds like the biological premise of the techniques such as Reverse Therapy, Amygdala retraining etc – an attempt to reset the malfunctioning HPA axis via specific interventions designed to calm these systems down…people regard these therapies as ‘psychology’ and disregard them – but in fact – they are not based on any current form of traditional psychology which views the mind separately from the body (a false dichotomy) and tarnishes CFS cases as ‘in the mind’. They are designed with an understanding that you can influence your physiology by harnessing the mind body connection…It makes sense to me. After quite a few sessions of RT and Amygdala RT I can often completely eradicate a symptom – from burning pain – to nothing. I dont know about other people – but in my case – its pretty clear that the regulatory systems are not functioning correctly and that there are specific reasons for this…however – its not easy gaining control over these systems because they are autonomic…peace!
I’m not nearly as good at that as you Steve – I can calm down some symptoms but not eradicate them (yet) – but my experience is similar. Something is driving what I feel is a kind stress tied sensory explosion in me, and I can at times calm that down and I feel much healthier. It’s slow and it does take a lot of work, but it does help. Congratulations on doing better.
I feel that here is great research, using a systemic, big-picture approach! I hope other researchers are paying close attention and will use this information to design even more intelligent research projects. Clearly the fact that many more women get this illness is significant, as is its persistence and consistency, year in and year out. I have had this for going on 20 years, and it seems to me that every single day I wake up with the same condition. No treatment or diet or special state of mind or anything else ever alters my basic condition, though I do have better or worse days depending on those and other transient variables. I have said it before: having this illness is like being a dog on a chain. The chain is long enough to move and make some little runs, but more than that and, “Snap!” I am back down. Whether I am at the end of my chain or not, I can always feel how I am tied. It took some years and all kinds of efforts to escape (treatment protocols, health regimens, etc.) to learn what the deal is.
It will be interesting to see if medical researchers ever figure out what could de-stabilize and reset the system back into a healthy pattern. It might even turn out to be a counterintuitive move, doing something completely different than what we might consider a healthy direction. Like the “Snap!” (there it is again) of the Chiropractor’s adjustment to get the spine back into alignment, this remedy might be odd and unwanted. In fact, however, it might not even be anything as active or stressful as that “Snap!”
Let’s look for this key. Not the key in the form of a bomb to drop on a pathogen (which might not be there), but the key in the form of how to change a systemic response….
This theory surely fits my experience. And like Steve, I found myself thinking of Amygdala training. In fact, this article may be the nudge that I’ve needed to commit to trying Amygdala training. Of course, I will continue with medicinal therapies that help, too.
cort, can you explain the cortisol awakening finding and direct me to that study you mention? Thanks
I always experience a major setback during my monthly period and have thought often that if i had been a male, i would have much quickly gotten better, because in between periods i experience an upward line. So this article makes much sense to me: it’s not the instigator, but it surely is a maintaining factor.
I would like to ask, If it is a pathogen i.e., http://en.wikipedia.org/wiki/Pathogenic_fungi, perpetuating this cycle, would this study help as a treatment to destroy the said pathogen. The properties associated possesses anti-fungal, anti-viral, translation-inhibiting and ribonuclease activities
http://www.sciencedirect.com/science/article/pii/S002432050000970X
Also I found this study relating to the same.
http://www.ncbi.nlm.nih.gov/pubmed/23963977
So could I ask Is this a possible treatment ???…
Please could you reply to my email address.
Kindest Regards
Marie
Low cortisol is not the cause. CFS patiënts have sometimes high levels of cortisol during daytime. There is one system which can calm down everything: The parasympathetic nervous system! CFS patiënts are in a constant state of stress. Why?
Broderick et al did note in the study that their model is incomplete in part because it doesn’t include the autonomic nervous system. Interestingly, though, they also said (if I read it right!) that they were confident that any more inputs to the model would not change the basic model; i.e. while aspects of the ANS and immune system could and should be added to the model they feel the core is quite strong. My guess that they would suggest both are present.
The female hormone system definitely throws an additional “spanner in the works” that doesn’t often seem to be considered by research. The extent of my ME/CFS/PEM changes with my monthly cycle quite predictably.
The concept of a new stable state really rang bells with me, if only we knew how to “nudge”…
The fact that there are “cluster” out brakes, and many may be part of a cluster and not know it, indicates a pathogen or a toxin is the culprit. Possibly in food or drink, in a public setting, effecting only those under stress and with a genetic profile.
My money is again with Lipkin and the gut.
Broderick et. al are careful not to say that their model addresses the cause. It’s more focused on the perpetuation of the illness. The cause, of course, would have to push the system off-kilter and he does believe that the immune evidence suggests a pathogen is present.
I have always believed that there is a hormonal link with ME/CFS – certainly for some of the female sub groups and perhaps male too, as I know a male with chronic lyme disease who has sub optimum cortisol levels.
I have had this illness for over 25 years (I am now almost 61) and even when it was in part remission (when I got back to 75% of my prior health) menstruation was problematic (and a few days pre and post menstruation) because symptoms returned and this situation worsened as I approached the menopause. I had a hysterectomy to try to stay at work but unfortunately this was the beginning of the end of my career and I was medically retired about 4 years later. Perhaps if I had kept my ovaries I would have fared better but hindsight is a wonderful thing! There must have always been some sort of hormonal issues for me because I was 16 before I had my one and only period until a GP I saw around that time put me on hormone therapy. I now have oestrogen patches, which are of some very limited value.
I had low cortisol levels when these were checked before I was medically retired and a sub optimum Synacthen test. However when Addisons disease was ruled out and the endocrinologist concluded that this was caused by ME, I was discharged – end of tests/assistance from the Endocrinologists.
I also have hypothyroidism, which was identified when I first presented with ME symptoms at the age of 35.
I really hope that there will be some research looking at the HPA axis and its altered state in ME/CFS and other illnesses with similar symptoms. I would be a willing volunteer in any such research as the illness seems to be getting more severe with every year that passes.
I still find the similarities between MS and ME/CFS so outstanding that I would not be surprised if the same systems and chemical interactions were not involved.
From what I have read from both MS and ME/CFS both Antigens(MS) / Pathogens(ME/CFS) may be triggering responses in the Immune (MS) / Auto Immune systems (ME/CFS).
The prevalence of people with MS or ME/CFS are further away from the equator this makes me conclude they live less drier regions of the earth where Molds maybe more prevalent and producing the Antigens and Pathogens involved ..
are we not looking at different sides of the same coin mabey ???>..
Your response on this would be very interesting. again to my email address please.
Some people have a natural immunity to pathogens and antigens and this is why only some become infected.
Both antigens and pathogens can be air borne giving a clear indication as to a causation of the clusters “Epidemics”.that have been identified.
However both antigens and pathogens can develop in enclosed places ie a persons home… giving rise to isolated cases from isolated exposure.
The chemical exchange processes of Hormonal differences in men and women ie Oestrogen vs Testosterone may be a significant finding. In-understanding the prevalence in women and the relief from symptoms women experience during pregnancy
Estrogens (also called Oestrogens) are steroid compounds
Testosterone is a steroid hormone from the androgen group
Steroid hormones help control metabolism, inflammation, immune functions, salt and water balance, development of sexual characteristics, and the ability to withstand illness and injury. The term steroid describes both hormones produced by the body and artificially produced medications that duplicate the action for the naturally occurring steroids
So maybe its not Hormones but the amount of “steroids” in a persons body that reduce symptoms.
thinking aloud there, and here we have evidence of that train of thought…..
http://patients.aan.com/resources/neurologynow/?event=home.showArticle&id=ovid.com:/bib/ovftdb/01222928-200905040-00008
So back to the MS and ME/CFS being very tightly related….
As well as the properties of Ginseng that I mentioned in my earlier mailing I think the properties of natural Honey should also be considered as a natural steroid.
Raw honey has anti-viral, anti-bacterial, and anti-fungal properties. It promotes body and digestive health, is a powerful antioxidant, strengthens the immune system, eliminates allergies, and is an excellent remedy for skin wounds and all types of infections. Raw honey’s benefits don’t stop there. Raw honey can also stabilize blood pressure, balance sugar levels, relieve pain, calm nerves, and it has been used to treat ulcers. Raw honey is also an expectorant and anti-inflammatory and has been known to effectively treat respiratory conditions such as bronchitis and asthma.
Many Body Builders are now realising the benefits as a natural Steroid too.
Mabey Nature gave us the problem but it could also give us the solution. After all most medicines are derived from Plant extracts….
I hope my posts today are useful.
Your responses would be very appreciated.
Kindest Regards
Marie
I don’t understand all of this – it’s quite above my head; however, what about cortisol? Is it possible to give that to sufferers so that it might push them over that threshold to get them back to the “real normal state”?
I also think some of this makes sense as it seems as though homeostasis is off kilter. I’ve had CFS for nearly 17 years (from age 35) and was diagnosed by Dr. Lapp. My illness was triggered by physical trauma (auto accident), not a virus. Any theory of causation that cannot account for onset like mine can’t be the answer. This research makes sense because it allows for various ways we’re thrown out of whack. I’m not sure we can say a pathogen keeps us from our previous normal state, unless it can happen in cases without viral onset? For instance, some existing pathogen takes advantage of our altered state and makes it hard for us to get back to normal?
@Carol: I’ve heard that ME/CFS patients can benefit from cortisol but only in the short term.
Given that much of the database comes from CDC’s Wichita Study, I’m surprised Broderick has managed to tease out what he has. But I still think this is a worthy goal, and I believe Vernon, Klimas, and Broderick are all too aware of the problem of feedback loops. Testosterone’s an example: after prescribing a patch, the doctor has to watch a guy’s levels because the body might overcompensate by lowering its own production.
This may one reason we don’t have MSH treatments available yet. ‘Sounds logical to supplement it if you’re low, as Shoemaker claims we all are, but for how long? Anything with individual variance now almost precludes funding an FDA study. (Woe to the kids inheriting this world.)
While men tend to be studied regarding many health issues, this study is yet another to suggest that males and females are not created equal. Women are studies pretty heavily when it comes to FM and ME/CFS leaving out their male counterpart. We know that men do not have the same issues with these disorders. Yet other health studies are predominately on males and we have had the notion that the same results apply to women. We are finding this just is not true at all.
I have never given up on the notion that the HPA axis dysfunction is present in both FM and ME/CFS. Cortisol disruptions in both, but the type of disruption is different. This is just one thing that suggests they are not interchangeable. Another factor to be considered is how cortisol levels are studies. For instance, the usual tests done to check for diabetes are not at all useful in determine insulin resistance. The same tests, but they need to be done at different times of the day with different challenges. I might conclude that this is the same for cortisol, thyroid function, and other metabolic and autonomic disturbances that occur as a result of a messed up HPA axis.
Well put, Celeste. I too have always felt (almost 20 years now) that the HPA axis is central to these disorders. Broderick is looking at the relationship between the adrenal and gonadal axes as it is known that all the endocrine axes are interconnected and affect each other. Is there anyone looking at the relationship between cortisol and dopamine as these two hormones are usually up at the same time which is why they send kids home from school at 3pm when the cortisol is low and so is the dopamine (a learning hormone and also a reward hormone.) Low dopamine means few rewards and these disorders certainly don’t give rewards and thus exacerbate the low dopamine. Perhaps this could be keeping the cortisol levels low. I know that when I get rewards in my life, my energy levels increase and any pain decreases. However, I seem to need a lot of rewards to keep me going. I have always believed that the maintaining of the sub-optimal state is caused by the hypothalamus as it controls most of the feed-back loops, sends out all the releasing hormones and plays a big part in control of the autonomic nervous system. It responds to all the changes in levels of hormones in the body and appears to always reset out of whack. My husband came up with this idea just from his observation of me over the years and it seems very logical to me. A Catch-22 or just a vicious circle, who’s to know?
From a different tack, Taylor et al suggested a different stress response in males to females and yes, Celeste, they were only testing men and presumed that females had the same response, therefore it has taken some time to wake up to the fact that females respond differently (for survival of the organism, of course!) Taylor et al suggested that the female had a tend-befriend response to stress and this involved an increase in oxytocin with a decrease in cortisol production with a calming effect needed to protect the children. So this maybe the stuck position that Broderick is suggesting. Men respond with a vasopressin increase and a cortisol increase. Apparently, vasopressin increases aggression in males, especially in the presence of testosterone. My hypothesis includes the possibility that severe stress in an infant female may result in development of a male response to stress, which means high cortisol levels and that possibly, after having children which enhances oxytocin production, that the stress response reverts back to female and gets stuck in that position (the hypothalamus being totally confused by now, lol!)
Below is a link to an article by Lauren A. McCarthy, Evolutionary and Biochemical Explanations for a Unique Female Stress Response:Tend and Befriend
http://www.personalityresearch.org/papers/mccarthy.html