Significance of XMRV Cortisol Receptors

[Wayne]

I've been wondering about the significance XMRV cortisol receptors. It has been mentioned several times, but I don't recall it being discussed in depth anywhere on this board. I take low-dose Cortef (cortisol) for severe adrenal insufficiency and would like to get a sense of whether these XMRV receptors might be a significant factor me.

I wonder if it might be an individual thing. I've posted fairly extensively on my own successful low-dose cortisol supplementation, but have heard from others, even those with severe adrenal insufficiency, that taking even the smallest amount of prescription cortisol gives them extremely negative reactions.

If anybody might have any special insights about this, or know where I might go for more information, I would appreciate hearing from you. -- Thanks.

Wayne

 

[SaraM]

cortisol

Hi Wayne,

I took cortef for 18 months and my muscle pain started gradually at the same time. Before that I had CFS without muscle pain and stiffness. Corttef can be a culprit in my case?I have no answer for that.

Sara

 

[fairlight]

Wayne-thanks for asking this question.

I had the same questions. I keep reading that XMRV has a cortisol receptor. What does that mean?

If I take any amount of prednisone my hair falls out, I want to eat everything in sight, especailly sweets, I gain weight very quickly and it puts me in a VERY bad mood. Even tiny amounts of cortef do the same thing. It also raises my eye pressure. I hope someone can tell us what the connection is to XMRV.

 

[jenbooks]

Well I don't know how many microbes have cortisol receptors--we could do a little pubmed or google search on that. It might be a common thing.

What it means is that when you produce cortisol (your stress hormone) it can bind to the virus and probably stimulates it to replicate.

If you are chronically stressed and have chronically elevated cortisol that's not good. Period. A healthy cortisol response is a spike in response to an acute stress, quickly dropping to baseline after the stress has passed. A chronically elevated cortisol will start higher, but worse, when there is an acute stressor, it will spike, and as it starts to fall, will spike again though not as high, like an echo stress response, before it goes to a baseline that is higher than a healthy persons anyway.

Some of this is genetic, I think. They tested kids with allergies and even when they weren't in hayfever season their cortisol levels were higher than normal.

 

[Wayne]

What it means is that when you produce cortisol (your stress hormone) it can bind to the virus and probably stimulates it to replicate.

Hi Sara, Fairlight & Jen,

Ruth mentioned on another thread that cortisol stimulates the replication rate in the XMRV virus. I know many of us deal with some pretty significant endocrine dysfunction, and this piece of information makes me wonder if the presence of the virus prompts our bodies to decrease cortisol production as sort of a protective measure.

I've long suspected that my adrenal glands might be just fine, but that my HPA axis is messed up and isn't sending my adrenals the proper signals. Now I wonder if this XMRV virus could be throwing a monkey wrench into this whole delicate HPA balancing act. One of my first instinctive thoughts when I heard about this virus was that if I do have it and could learn to control it, I would probably be able to stop taking my Cortef. I guess we'll see. Thanks much for all your responses.

Best Regards, Wayne

ETA -- BTW, does anybody know what a monkey wrench is?

 

[mojoey]

I agree

with Jen. And funny you mention that Wayne.. I was just gonna guess that it has to do with replication rate. Also, it wouldn't surprise me if the cortisol stays low as an adaptive measure...sorta like cheney's theory on oxygen toxicity and diastolic dysfunction.

I think any successful long-term therapy really needs to address both the CNS (and hence the HPA) and immune modulation to have any chance of sustained systems balance. Sustained is really the key word.

Yes of course we know what a monkey wrench is...simian virus right?

 

[jenbooks]

very witty mojo

Yes of course we know what a monkey wrench is...simian virus right?

Very funny

 

[Wayne]

XMRV Cortisol Receptors - Monkey Wrench

Well I don't know how many microbes have cortisol receptors--we could do a little pubmed or google search on that. It might be a common thing.

Hi again Jen,

I had a thought after I read your note. Perhaps a number of viruses that can become activated because of our immune system dysfunction also have cortisol receptors. If so, this could explain many of the symptoms we experience which reflect a lack of cortisol in our system.

But as Joey mentioned, our bodies could very well be keeping cortisol levels low as an adaptive measure. Of course, I guess it could be some kind of combination of the two. BTW Joey, loved your definition of monkey wrench. LOL. Some good "middle of the night" humor.

Wayne

 

[heapsreal]

cortisol

cortisol is immunosuppressive, maybe helps it avoid immune system

 

[Alice Band]

People with CFS have low cortisol, particuarly in the morning. That's opposed to people with depression who can have high cortisol.

It may be that the low cortisol found in CFS is some sort of protective state.

Cheney theorised years ago that CFS people had high cortisol to start out and then it switched to low cortisol, although there has been no science to back this up and like many of his early theories may have been discarded. I think he is a great doctor and I don't mean any disrespect by this.

Too soon to tell all the reasoning around this maybe?

 

[Daisymay]

cortisol

Surely having a chronic viral infection is of itself stressful and must affect cortisol production, so even without people endutring any particularly stressfuleventrs in their lives having CFS is very stressful to the body this may of itself lead to release of cortisol.

I do find it annoying when pschaitrists talk of PWCFS not being able to deal with stress, well if you are so ill your body is already under a lot of physiol ogical stress so any stress on top can be too much and too much may well be doing something very enjoyable but it is too much for the body, nothing to do with being stressed in the common everyday notion of stress.

Also perhaps some viruses have evolved to use this fact that infection equals stress equals cortisol equals something they can evolve to use for their benefit to help them reproduce?

 

[Alice Band]

Daisymay,

That doesn't happen with CFS and we are talking about CFS here. Research has shown that cortisol is low. I've had mines tested and it is low all day but especially in the morning.

The only doctor who finds some high cortisol in his "cfs" patients is Simon Wessley

 

[Daisymay]

cortisol

I was n't meaning we had high levels, sorry if it cam eover as that, I am aware of the research and all to aware of Wessely, but perhaps at the start of the infection we produce higher levels of cortisol and then the levels go down as an adaptive move to try and negate the infection, but even then when we are under any degree of stress, cortisol levels will go up a bit and even that is enough to help to feed the infection?

 

[richvank]

Cortisol in CFS

Hi, all.

Before people become ill with CFS, most seem to report that they were able to cope with stress alright, and some were able to handle a lot of it. That being true, I think we have to assume that their HPA axis function was fairly normal at that time. If so, it means that under stress, their cortisol level would have been elevated. People don't tend to have their cortisol levels measured until they are well into CFS, but some have, and I have seen some that are high in the early stage of CFS.

As has been noted already here, after a person has been into CFS for a while, often the cortisol level drops compared to the normal diurnal variation.

For what it's worth, the GD-MCB hypothesis suggests that this drop results from glutathione depletion in the pituitary gland. Glutathione depletion has been found in the blood plasma in CFS patients, and it is associated with a partial block in the methylation cycle. Direct measurements of glutathione have not been made in the pituitary, but there is reason to believe, based on the systemic biochemistry of glutathione, that it is low in many of the organs.

The reasoning by which low glutathione in the pituitary would cause lowered cortisol levels is as follows:

Normally, the pituitary produces ACTH, which travels via the blood to the adrenals, and controls their release of cortisol to the blood. ACTH is made as part of a molecule called POMC (proopiomelanocortin). This molecule has a tail that incorporates a "hook" the structure of which is stabilized by two cystine double bonds. In order to form these bonds properly, it is necessary that cysteine residues in the molecule be maintained in the chemically reduced state until the appropriate time, when chaperone molecules join the proper partners together. Glutathione is needed to maintain this reducing redox state in the cytosol (main part of the cell matrix). When glutathione becomes depleted, this mechanism becomes dysfunctional, and the secretion of ACTH by the pituitary becomes dysregulated, and then decreases. According to this hypothesis, that is what causes the HPA axis dysfunction in CFS.

If this is true, lifting the methylation cycle block, which allows glutathione to come back up to normal, will correct the HPA axis dysfunction. There is some anecdotal evidence that this is true, but it has not been subjected to controlled study.

I'm not sure yet how this would tie in with the XMRV virus. If this virus is indeed stimulated to propagate by high cortisol, it may be that it would flare at the onset of CFS in people who have the virus on board. I'm speculating here, but perhaps that could account for the "viral" type presentation at the onset of "sudden onset" cases of CFS.

I understand that in order for the XMRV virus to propagate, it is necessary for cystine (disulfide) bonds to form in some of its structural protein. This would also require depletion of glutathione, I think, so the plot thickens some more . . . . I'll be very interested to learn more about this virus as time goes on and more research can be done. It could help to fit a lot of the pieces we already have together.

Best regards,

Rich

 

[Mark]

Kicking You When You're Down

So putting it all together then...cortisone suppresses the immune system, and cortisone also activates XMRV to replicate. When cortisone goes up, the immune defences are temporarily lowered somewhat - perhaps to divert resources to 'stressful' life - and then the virus comes out to play. Makes sense, no? Wouldn't you want to do that if you were a virus? It also likes to grow when you have inflammation (which covers all kinds of things) or high levels of hormones (I'll leave you to think through the implications of that, but don't forget how it's likely to be transmitted...).

One can imagine how the body might respond to the fact that it's being attacked whenever it lowers its guard (which it must do in order to get stuff done out in the real world)...by reaching either a state where cortisone levels are permanently crashed (don't give it cortisone to breathe...eg by lying around doing nothing all day) or alternatively, cortisone levels rise during the day as normal, as you go about your life, helping the virus to replicate until it overwhelms you again, then once you get to sleep and cortisone is lowered again, the immune system is appalled by all the virus it finds and crashes the cortisone so it can get to work...and you wake up the next morning - or afternoon - with zero cortisone and back to square nought.

I think many of us will recognise BOTH these patterns, as the 'rock and the hard place' between which sufferers are caught. Seems to fit well to me, but I'm not a scientist so some of that might be a bit off...but I reckon it's along those lines.

Oh yeah and what Wessley says has got nothing to do with nothing, who listens to him any more? I heard he was going into therapy...

 

[Dreambirdie]

Really interesting, Rich. Thanks for your post. It makes sense to me, as I have pretty severe MCS as well as CFS. I have noticed over the years, that whenever my adrenals are in better shape, not only do I deal with stress better, but I also I feel less reactive to chemicals and toxins.

IN regard to this, I'm still eager to get a reply from you to a question I posted a while back on another thread. I'm wondering if taking N-A-C "cancels out" the effectiveness of the folates and the B12, as Freddd insists it does? What is your take on this. When I get toxic releases of heavy metals, which I do when on the B12 protocol, the N-A-C rescues me quite effectively. I can't afford to not take it. SO I'm hoping they can work okay together.

 

[richvank]

To dreambirdie re: NAC

Hi, dreambirdie.

I think that how a PWC will react to NAC while on treatment involving B12 and active folate will depend on their genomic inheritance, on their body's ability to process sulfur-containing substances, and on their mercury body burden.

As I've posted in the past with respect to what freddd has posted about his own case, I think that his genomic situation is somewhat different from that of most people who have CFS, in that it appears that his cells do not have normally functioning B12 processsing enzymes. I think this is why he does not receive benefit from taking hydroxocobalamin, and also why he experiences problems if he takes glutathione or its precursors. NAC can act as a precursor for glutathione synthesis, because it supplies cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione.

Normally, the cells are able to use any form of B12 and to convert it to the two active coenzyme forms it needs to carry on its normal metabolism. Freddd has found that he needs to take the two coenzyme forms of B12 directly, in fairly large dosages, and on a continuous basis. I think that what he is doing in this way is overcoming his cells' inability to process B12 normally, and supplying the final forms of B12 that they need directly. It is very fortunate for him and that he has found this solution, and it is also very fortunate that the cells are able to respond to the active forms of B12 supplied in this way. There is a small amount of discussion in the published medical literature about this type of treatment in others who have these genomic issues.

I think that the reason freddd does not do well if he takes glutathione or its precursors is that (as he has suggested) the glutathione binds the B12 to form glutathionylcobalamin. This is a normal reaction in the body, and normally it is beneficial, because it protects the B12 in the cells from reacting with other substances in the process of converting it to the two active forms. However, in freddd's case, apparently because he has genomic issues with his processing enzymes, his cells are not able to convert glutathionylcobalamin to the active coenzyme forms of B12, and thus the B12 becomes trapped in a form that his cells cannot use. This intolerance of glutathione provides an important clue that at least part of freddd's genomic issues are downstream of glutathionylcobalamin in the normal B12 metabolism.

For people who do not have these genomic issues, this will not be a problem. Hydroxocobalamin will work alright for them, and glutathione will not block their use of B12. However, as freddd has pointed out, if a person has a serious lack of methyl groups, the cells will have difficulty converting other forms of B12 to methylcobalamin. Dr. Amy Yasko has recognized this in her treatment program, and for some genomic situations, she recommends use of methylcobalamin rather than hydroxocobalamin. She also includes a small amount of TMG in her multi, which will encourage the alternative BHMT pathway in the methylation cycle, thus forming SAMe to supply methyl groups. In my suggestion of the Simplified Treatment Approach, I stayed with hydroxocobalamin to avoid any possible problems with reaction with mercury to form methylmercury. It's possible that I was overly cautious in doing so, as freddd has argued, but I try to err on the side of caution. I note that some of the people who started out with the Simplified Treatment Approach have subsequently switched to methylcobalamin, and at least one has reported benefit from doing so.


Another possible problem with taking NAC is that it will increase the load of sulfur metabolites, and thus increase the flow through the sulfite oxidase enzyme, to form sulfate, which is one of the excretion forms of sulfur in the urine. Some people have a backlog at that point in the pathway, either because of genomic issues with this enzyme, or because of a lack of enough molybdenum, which forms a cofactor for this enzyme, or because they have a significant population of sulfate-reducing bacteria in their gut, which are producing hydrogen sulfide, which also ends up loading the sulfite oxidase enzyme. If these problems are not present, this will not be an issue.

The final possible problem with NAC is that it has been found by Aposhian et al. in rats to be able to transport mercury into the brain. For people who have a significant body burden of mercury, this can be bad news. Dr. David Quig has recommended that the NAC dosage be no greater than 300 mg per day if there is believed to be a significant body burden of toxic heavy metals.
Dr. Cheney has spoken of two cases in which PWCs took large dosages of NAC and subsequently committed suicide. This is anecdotal, and the following is unproven, but it may be that they moved a lot of mercury into the brain.

You mentioned that NAC appears to rescue you from what you think is mobilization of mercury. I think this is possible. Some of the NAC will be converted into glutathione, and glutathione is what the body normally uses to conjugate mercury so that it can be excreted.

I'm glad to hear that NAC helps you, and I think it means that you probably don't have any of the issues I've discussed here. We are dealing with a very heterogeneous population in CFS, so that different people have different responses to things. I try to be careful not to claim that one size fits all. The more cases I study, the more variations I see. I think it's fortunate that a B12-folate type of treatment helps as many people as it does.

Sorry I didn't get to your question earlier.

Best regards,

Rich

 

[Alice Band]

Thanks Rich, it's good to have you here and thinking through how it could all be working (or not)!

 

[dannybex]

Hi Alice...

People with CFS have low cortisol, particuarly in the morning. That's opposed to people with depression who can have high cortisol.

It may be that the low cortisol found in CFS is some sort of protective state.

Cheney theorised years ago that CFS people had high cortisol to start out and then it switched to low cortisol, although there has been no science to back this up and like many of his early theories may have been discarded. I think he is a great doctor and I don't mean any disrespect by this.

Too soon to tell all the reasoning around this maybe?

Hi Alice,

Well, all I can say is when I was tested in 2003, I had high cortisol throughout the entire 24 hour, 4-sample salivary cortisol test. I could still get up at a reasonable hour, and didn't have to nap as much. The doc then said that my adrenals were fighting to keep me going, so were overproducing cortisol at that time.

Six years later, I fight tending to stay up late at night, and have had an increasingly difficult time even getting out of bed in the morning. While I haven't been able to afford a new test, I am guessing my cortisol, at least in the AM, is lower.

d.

 

[Robin]

So putting it all together then...cortisone suppresses the immune system, and cortisone also activates XMRV to replicate.

That is a very interesting hypothesis. Extending it beyond the diurnal cycle, you could suppose that the virus replicates during periods of high cortisol/stress (death of a loved on, loss of of a relationship, financial pressures, or just being very ill) which would precipitate a relapse of more severe symptoms, while during periods of lower cortisol/stress the virus replicates less and thus creates a state supportive of healing? That would explain the mind/body theory.

Cortisol effects many other hormones and chemical processes in the body and is just beginning to be studied and understood. A friend of mine researches neuroendocrinology with a focus on cortisol, I'll ask him if he knows anything about it in relation to virology.