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HPA Axis Reboot.

adreno

PR activist
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4,841
Right. Whether the rooibos would have beneficial results in the long run by "resting" the adrenals, or perhaps altering glucocorticoid & steroid receptor sensitivity, is unknown to me. Maybe someone who is more of an expert on adrenals would know the answer to that.
Yes, it's possible that by suppressing cortisol even further, the HPA axis could switch to a higher set point. At least this is what this article suggests:

A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline.
Bear in mind that this theory is based on a mathematical model only.
 

jeffrez

Senior Member
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1,112
Location
NY
Yes, it's possible that by suppressing cortisol even further, the HPA axis could switch to a higher set point. At least this is what this article suggests:


Bear in mind that this theory is based on a mathematical model only.

That's exactly the theory I was thinking of, adreno. In their model, however, I believe they blocked cortisol receptors, *while also increasing ACTH.* I believe those two conditions are necessary in their idea to reset the base point, but it's been a year or more since I read their paper. I'm not sure the rooibos would do that, so I'm still unclear on whether it would work in that way.

I suppose if someone is drinking the tea long term and not noticing any negative effects it might be beneficial - cortisol receptors might get resensitized, upregulated, etc. - but again, I'm hesitant to say that w/out knowing for sure. Wouldn't it be great if we could improve just by drinking rooibos for a few months & resetting the HPAA? Especially with all the other great benefits of rooibos. But for now, w/out knowing what the long term effects might be, I'm banking more on the adaptogens, like in the excellent list Ema posted.
 

adreno

PR activist
Messages
4,841
That's exactly the theory I was thinking of, adreno. In their model, however, I believe they blocked cortisol receptors, *while also increasing ACTH.* I believe those two conditions are necessary in their idea to reset the base point, but it's been a year or more since I read their paper. I'm not sure the rooibos would do that, so I'm still unclear on whether it would work in that way.

I suppose if someone is drinking the tea long term and not noticing any negative effects it might be beneficial - cortisol receptors might get resensitized, upregulated, etc. - but again, I'm hesitant to say that w/out knowing for sure. Wouldn't it be great if we could improve just by drinking rooibos for a few months & resetting the HPAA? Especially with all the other great benefits of rooibos. But for now, w/out knowing what the long term effects might be, I'm banking more on the adaptogens, like in the excellent list Ema posted.
Well, at least under normal conditions, when steroid production is inhibited at the glandular level, the pituitary should turn up ACTH on it's own, in an attempt to increase production. In the study I quoted they imagined using CBG to bind cortisol, and thereby increase ACTH output. I'm not very familiar with rooibos, but from what I could glance from the abstract it looks like cortisol is inhibited at the glandular level, so in theory I guess it could work.

I have already tried drinking rooibos regularly (about 1 cup daily) but didn't notice much of an effect. I suspect we will need at pretty hefty dose I we hope to reset the HPA axis. I also suspect that the period before ACTH production will be turned up would be very unpleasant.
 

jeffrez

Senior Member
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1,112
Location
NY
Well, at least under normal conditions, when steroid production is inhibited at the glandular level, the pituitary should turn up ACTH on it's own, in an attempt to increase production. In the study I quoted they imagined using CBG to bind cortisol, and thereby increase ACTH output. I'm not very familiar with rooibos, but from what I could glance from the abstract it looks like cortisol is inhibited at the glandular level, so in theory I guess it could work.
I have already tried drinking rooibos regularly (about 1 cup daily) but didn't notice much of an effect. I suspect we will need at pretty hefty dose I we hope to reset the HPA axis. I also suspect that the period before ACTH production will be turned up would be very unpleasant.

I've tried it, too, but like you not for extended periods.

Your comments prompted me to go back & read the entire study again. It seems that theoretically rooibos actually could perhaps work:

Cortisol output of the HPA axis can in reality be manipulated either directly or indirectly through several interventions. The most direct approaches involve (1) inhibition of cortisol synthesis at the level of the adrenal gland...
However, there might also be side effects similar to what they mentioned, "decreased androgen and aldosterone synthesis... hypoadrenalism," etc.
These portions seem relevant:
Note that the optimal input does indeed bring the system to the healthy steady-state point. This is done while maintaining a circulating cortisol concentration that is near the steady-state value with the exception of a rapid drop at the start of treatment. The optimal control solution as computed under the MPC framework has several key features. The cortisol concentration is rapidly dropped at the outset. Once this drop in cortisol concentration is achieved, the system requires little additional control action to come to steady state. This qualitative information can be used to formulate a suboptimal control strategy that will bring the system to the healthy steady state
The MPC solution suggests that manipulating cortisol concentration is a plausible strategy for redirecting the HPA axis to a healthy steady state. The key difficulty in applying this approach is determining when the cortisol concentration has been sufficiently lowered with regard to the other state variables to allow the system to return to a healthy equilibrium. That is, one must identify an observable event (corresponding to a measurable variable) which signals that the steady state of the system has shifted.
Treatment 1 The cortisol concentration in the system should be slowly decreased until ACTH levels (x2) have increased by more than 30% relative to the initial condition. Once this signal is observed, the system's own natural feedback control action should restore cortisol levels to normal
A positive outcome may also be obtained by applying even less severe levels of cortisol suppression and extending the duration of the treatment. ... Nonetheless there exists a minimum level of cortisol suppression below which the treatment fails regardless of how long conditions are maintained. Conversely there also exists a minimal treatment duration below which even severe levels of cortisol suppression will prove unsuccessful in restoring normal hormone levels.


So a few points to consider would be whether the rooibos could lower cortisol sufficiently to allow the reboot. From the earlier study showing 4-fold reduction in steroid output, and the comment here that less severe reductions of cortisol but for longer periods might also work, it seems like perhaps it could.

Another point is that one cup per day might not be a proper dosing schedule to work, even if the amount per cup was sufficient. It might require a steady input of rooibos at regular intervals throughout the day (e.g., every 6 or 8 hrs) to maintain the low levels consistently.

The other practical questions would be how to know that the cortisol had been lowered enough & ACTH raised enough (30% of start) to effect the shift. Increasing ACTH 30% of normal should cause an increase in anxiety, no? Esp. if cortisol steroidogenesis is still blocked or reduced. So perhaps that would be a subjective marker of when it's time to stop the tea.

Thoughts?

p.s. Not sure what's up with formatting. The quotes all got pasted in different font sizes. I selected everything and set the entire post to a single font size, but it didn't seem to work. Removed space btwn paragraphs that didn't seem to help, either. Apologies for readability issues.
 

adreno

PR activist
Messages
4,841
I do thou wonder if the low abnormal cortisol levels affect me anyway, as when I was on prescription drugs to raise cortisol (before I was drinking rooibos).. that didnt help me get any better anyway.
So maybe my body dont really care what level my cortisol is at, cause of other major things going on.....
Yes, I wonder about this, too. I was on cortisol supplementation for two months, and though I did notice some improvements, it was nowhere near a resolution of my symptoms. When I was on mirtazapine however, which actually lowers cortisol, I never felt better physically. It just about abolished my POTS, which cortisol didn't. I also feel quite good on Holy Basil, which also lowers cortisol.

The point is that we might be putting too much emphasis on the importance of cortisol. Studies have consistently found hypocortisolism in ME/CFS to be mild, and nothing like Addison's, which is of course very serious and life threatening.

There is also the possibility that cortisol is relatively low in ME/CFS for adaptive/compensatory reasons, and that bringing cortisol levels up could actually have a detrimental effect. One problem might be that cortisol shifts immune balance towards TH2 dominance, which will make it harder for the body to fight viral infections.

Before supplementing cortisol, I tried adrenal glandulars for about six weeks. At first they abolished my symptoms and I felt wonderful. Then suddenly, from one day to the next, I developed very bad POTS. This is three years ago, and I never recovered. I don't know why, maybe the increased cortisol reactivated a latent viral infection, but I am just guessing. Cheney warns that adrenal glandulars is the worst thing you can give to a ME/CFS patient.

The upshot is that we are pretty much in the dark here. It's anyone's guess if increasing cortisol levels is really a good idea or not. It most certainly isn't going to be a cure, though.
 

adreno

PR activist
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4,841
So a few points to consider would be whether the rooibos could lower cortisol sufficiently to allow the reboot. From the earlier study showing 4-fold reduction in steroid output, and the comment here that less severe reductions of cortisol but for longer periods might also work, it seems like perhaps it could.

Another point is that one cup per day might not be a proper dosing schedule to work, even if the amount per cup was sufficient. It might require a steady input of rooibos at regular intervals throughout the day (e.g., every 6 or 8 hrs) to maintain the low levels consistently.

The other practical questions would be how to know that the cortisol had been lowered enough & ACTH raised enough (30% of start) to effect the shift. Increasing ACTH 30% of normal should cause an increase in anxiety, no? Esp. if cortisol steroidogenesis is still blocked or reduced. So perhaps that would be a subjective marker of when it's time to stop the tea.

Thoughts?
I really don't know what to tell you. I agree with all your thoughts here. It will be difficult to subjectively judge when cortisol is suppressed enough to reset the HPA axis. We are in uncharted territory here.

I also think it's important to remember that this is just a data model, and we have no idea how it will pan out in real life. Maybe the increased ACTH will just lead to desensitization of ACTH receptors, or CRH release will be lowered via feedback inhibition. If the lowered cortisol output seen in ME/CFS is indeed adaptive, we can expect the body to try its hardest to bring cortisol levels back down again. And as I said to tania, we don't even know if bringing cortisol levels up will lead to any positive long term effects, or make things worse.
 

jeffrez

Senior Member
Messages
1,112
Location
NY
I really don't know what to tell you. I agree with all your thoughts here. It will be difficult to subjectively judge when cortisol is suppressed enough to reset the HPA axis. We are in uncharted territory here.

I also think it's important to remember that this is just a data model, and we have no idea how it will pan out in real life. Maybe the increased ACTH will just lead to desensitization of ACTH receptors, or CRH release will be lowered via feedback inhibition. If the lowered cortisol output seen in ME/CFS is indeed adaptive, we can expect the body to try its hardest to bring cortisol levels back down again. And as I said to tania, we don't even know if bringing cortisol levels up will lead to any positive long term effects, or make things worse.

Those are all good points. In my case, CFS started from a doc improperly taking me off prednisolone, without any taper. I had a massive attack of adrenal insufficiency the next day, and after that the fatigue just never improved, with endurance levels then much lower and PEM. A few "crashes" over the years all seemed to be related to depleted cortisol & stress events, and indeed, going on licorice extract and adrenal cortical extracts made some of the biggest difference in symptoms up to that point.

I had an immune reaction to a supplement, with fever & swollen glands for a few days a couple years ago, from which the CFS got much worse, so maybe resetting HPAA wouldn't help with that aspect, or perhaps that only happened b/c of depleted cortisol to begin with. Like you said, we're in largely uncharted territory here.

But for me, hypoadrenal & low cortisol levels have seemed to be central to everything, with salivary cortisol tests always showing not only lowered cortisol, but a normal cortisol curve, only many standard deviations below normal. That's what led me to believe the "steady state" theory might have some validity, as my curve is normal but apparently only at a lower set point. Whether rebooting that back to more normal levels would improve most/all symptoms, whether it would be possible to reboot it, whether like you say ACTH receptors or CRH functioning would be downregulated are all unknowns at this point.

I have to wonder, though, if these "crashes" - which typically have lasted average of 2-4 weeks - aren't representative of HPAA resetting itself after a period of obviously lowered cortisol release. I doubt that's the entire picture, but just disagreeing with you a little on this one point, I don't see how improving something that's dysfunctional could in most cases be a bad thing. Especially something so central to functioning as adrenal hormone output.

Personally, I'm fascinated with this idea, and it seems to make so much sense on a gut level. That doesn't necessarily mean anything, but even at the most primitive level of thinking about it, I've often reflected that *adding* cortisol/prednisolone/steroid, etc is what caused this for me, so it would only seem to make sense (subsequent damage notwithstanding) that doing the opposite should help. The question has always been how to do that - I even bought mifepristone (aka, RU-486, glucocorticoid receptor antagonist) from Israel a couple years ago with the idea of trying this out, but got too scared to take it in case it permanently downed my HPAA even more. But with the rooibos seeming to be a much gentler approach, and the <strike> research </s> theoretical model saying that a lesser inhibition over a longer time could theoretically also work, maybe that would be something to try. All those anti-oxidants wouldn't hurt, either. : -)
 

adreno

PR activist
Messages
4,841
Personally, I'm fascinated with this idea, and it seems to make so much sense on a gut level. That doesn't necessarily mean anything, but even at the most primitive level of thinking about it, I've often reflected that *adding* cortisol/prednisolone/steroid, etc is what caused this for me, so it would only seem to make sense (subsequent damage notwithstanding) that doing the opposite should help. The question has always been how to do that - I even bought mifepristone (aka, RU-486, glucocorticoid receptor antagonist) from Israel a couple years ago with the idea of trying this out, but got too scared to take it in case it permanently downed my HPAA even more. But with the rooibos seeming to be a much gentler approach, and the <strike> research </s> theoretical model saying that a lesser inhibition over a longer time could theoretically also work, maybe that would be something to try. All those anti-oxidants wouldn't hurt, either. : -)
I have quoted the following study in another thread:

Effects of intestinal microbiota on anxiety-like behavior.
Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.

So this is an example of how the immune system controls the HPAA. This is one example of how the model study is very simplified and isolated, i.e. the model does not take into account interaction with other biological subsystems. It is my personal belief that the immune system is where you have to do modulation, and also that the HPAA will never by normalized until the immune system is. But I could of course be wrong. In any case, I will be very interested in hearing your experiences if you decide to try it.

BTW, a glucocorticoid receptor antagonist probably won't work, because mineralcorticoid receptors are equally, if not superiorly, involved in feedback inhibition.
 

jeffrez

Senior Member
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1,112
Location
NY
I have quoted the following study in another thread:

Effects of intestinal microbiota on anxiety-like behavior.


So this is an example of how the immune system controls the HPAA. This is one example of how the model study is very simplified and isolated, i.e. the model does not take into account interaction with other biological subsystems. It is my personal belief that the immune system is where you have to do modulation, and also that the HPAA will never by normalized until the immune system is. But I could of course be wrong. In any case, I will be very interested in hearing your experiences if you decide to try it.

BTW, a glucocorticoid receptor antagonist probably won't work, because mineralcorticoid receptors are equally, if not superiorly, involved in feedback inhibition.

Couldn't agree with you more that an immune component is closely linked to HPAA, and to other brain function. To what extent that's only a 1-way street w/HPAA is less certain to me. Think there is flexibility there from both directions.

Not sure also how CFS could not be present one day, and then suddenly present the next w/only difference being a drug that directly affects HPAA - directly only affects glucocorticoid receptors, in fact. That's what made me think a GR antag itself would do it. Still not unconvinced of that, but the fact that rooibos impairs other steroid pathways too probably makes it an even better choice.

Thx 4 all your comments on this, btw. Really interesting & informative.
 

taniaaust1

Senior Member
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13,054
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Sth Australia
One problem might be that cortisol shifts immune balance towards TH2 dominance, which will make it harder for the body to fight viral infections.

adreno.. is that a theory of cortisol shifting TH2 dominance.. or is it something actually known that it shifts it towards the TH2?
 

Adster

Senior Member
Messages
600
Location
Australia
This is interesting, thanks for all the research work you are doing. It's particularly interesting to me because I know my body can work ok if given the right control signals(ie when I catch a head cold). So the working components aren't stuffed, yet.
 

adreno

PR activist
Messages
4,841
adreno.. is that a theory of cortisol shifting TH2 dominance.. or is it something actually known that it shifts it towards the TH2?
Yes, this is known:
Ann N Y Acad Sci. 2004 Jun;1024:138-46.

Glucocorticoids and the Th1/Th2 balance.
Elenkov IJ.

Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room 2D46, 10 Center Drive, Bethesda, MD 20892, USA. Elenkovi@mail.nih.gov

Abstract

Evidence accumulated over the last 5-10 years indicates that glucocorticoids (GCs) inhibit the production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells. Through this mechanism increased levels of GCs may systemically cause a selective suppression of the Th1-cellular immunity axis, and a shift toward Th2-mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic GCs through induction of a Th2 shift, may actually protect the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines and other products of activated macrophages with tissue-damaging potential. However, conditions associated with significant changes of GCs levels, such as acute or chronic stress or cessation of chronic stress, severe exercise, and pregnancy and postpartum, through modulation of the Th1/Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/allergic diseases.

PMID: 15265778
 

Enid

Senior Member
Messages
3,309
Location
UK
If this is controlled by the Thyroid gland - interestingly I had a late diagnosis of thyroid function problems (by at least a year) before ME onset (from sore throat/flu like symptoms which wouldn't go away). High doses thyroxine needed initially too.
 

justy

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Not up to getting into this too much at the moment. Not sure what my cortisol levels are - i do know my health was destroyed by steroids that i was left on for too long (bothj inhaled and oral)

My point is about roobois tea - i have been drinking this at a rate of perhaps 6 -8 cups a day for years with no effect whatsoever. I drink it because i like it and always thought that i was at least getting a good dose of antioxidants. Well that wasnt true either as testing a couple of years ago showed a severe deficiency of antioxidants in my body.
All the best, Justy
 

jeffrez

Senior Member
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Location
NY
Not up to getting into this too much at the moment. Not sure what my cortisol levels are - i do know my health was destroyed by steroids that i was left on for too long (bothj inhaled and oral)

My point is about roobois tea - i have been drinking this at a rate of perhaps 6 -8 cups a day for years with no effect whatsoever. I drink it because i like it and always thought that i was at least get--ting a good dose of antioxidants. Well that wasnt true either as testing a couple of years ago showed a severe deficiency of antioxidants in my body.
All the best, Justy

6-8 cups a day? Wow, I guess there goes that idea. Maybe that study was just junk basically to sell the latest supplement fad. It happens. What kind of antioxidants were you tested for?
 

Hanna

Senior Member
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Location
Jerusalem, Israel
Hi,
Like Justy I was a heavy roobois tea drinker (1 liter/day routine and more...) for 2-3 years. I didn't see any positive change. And had to stop because of a fairly marked thiamine deficiency that was discovered in 2011 and may have been linked to this habit for a long looong period.
 

justy

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6-8 cups a day? Wow, I guess there goes that idea. Maybe that study was just junk basically to sell the latest supplement fad. It happens. What kind of antioxidants were you tested for?

Or maybe i am the anomoly?

I did the mitochondrial function profile test with acumen labs - it gives you a good idea of antioxidant status by looking at various things -(cant remember exactly) my antioxidant status was appaling. Very very low co q 10, very high cell free DNA, borderline B12 plus a partial blockage on the SODase gene and low glutathione.

All the best, Justy
 

jeffrez

Senior Member
Messages
1,112
Location
NY
Or maybe i am the anomoly?

I did the mitochondrial function profile test with acumen labs - it gives you a good idea of antioxidant status by looking at various things -(cant remember exactly) my antioxidant status was appaling. Very very low co q 10, very high cell free DNA, borderline B12 plus a partial blockage on the SODase gene and low glutathione.

All the best, Justy

That's interesting - sounds like a very useful test. Do you supplement with co q-10 & b12 now, and if so did you see any effects from it?

I might be wrong, but think the antioxidants in things like rooibos and green tea and the like are more from polyphenols and related substances than glutathione or SOD boosters, etc. It might be that with low Aox status you are therefore even more benefited by taking the tea - although I have to admit I've never had an improvement from taking "antioxidants," except glutathione through IV. I'd like to think we could all just take handfuls of antioxidants and see immediate improvement, but it doesn't seem to work that way unfortunately!