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Mifepristone for ME/CFS? (NK Cell Function / HPA Reset)

Hip

Senior Member
Messages
17,824
confused why anyone would want to block progesterone, i thought progesterone helped with the toxic effects of estrogen

Blocking the progesterone receptor is not the reason why mifepristone might help ME/CFS; it's the blocking effect this drug has on the glucocorticoid type II receptor that is thought to produce the HPA-axis reset.

Some studies have shown that taking mifepristone for just 4 days (at a daily dose of 600 mg) is enough to trigger a HPA-axis reset. So you are not taking this drug for very long.
 

frozenborderline

Senior Member
Messages
4,405
ok sick. someone messaged me on reddit and told me they thought CFS was all an HPA axis problem. I have to admit it seemed like something the psych crowd would push/seemed like a little quack-ish. That said I definitely have low cortisol and high DHEA
 

Hip

Senior Member
Messages
17,824
I have to admit it seemed like something the psych crowd would push/seemed like a little quack-ish.

It does a bit, but I think the idea of an HPA-axis reset relates more to the feedback loops that are involved in the HPA-axis; the idea is that the HPA-axis may become perturbed from its normal homeostatic equilibrium, and then its own feedback loops maintain that disequilibrium. But the theory is that a reset allows a return to the normal equilibrium state.

However, there seems little science to back up these ideas. And I don't generally subscribe to the notion that physiology can be throw out of homeostatic equilibrium, and once this happens, it can maintain itself in this out-of-equilibrium state, in a self-sustaining way, until such time as it is reset, which then fixes the problem.

I don't generally subscribe to this, as I am not aware of any system in the body we know of that follows this pattern. Rather, I tend to think that if a physiological system is out of its normal equilibrium, there is a specific cause to this, and the disequilibrium will not be fixed until the cause is addressed.


That said, I may still experiment with a mifepristone HPA-axis reset, as I've nothing to lose in trying.
 

frozenborderline

Senior Member
Messages
4,405
It does a bit, but I think the idea of an HPA-axis reset relates more to the feedback loops that are involved in the HPA-axis; the idea is that the HPA-axis may become perturbed from its normal homeostatic equilibrium, and then its own feedback loops maintain that disequilibrium. But the theory is that a reset allows a return to the normal equilibrium state.

However, there seems little science to back up these ideas. And I don't generally subscribe to the notion that physiology can be throw out of homeostatic equilibrium, and once this happens, it can maintain itself in this out-of-equilibrium state, in a self-sustaining way, until such time as it is reset, which then fixes the problem.

I don't generally subscribe to this, as I am not aware of any system in the body we know of that follows this pattern. Rather, I tend to think that if a physiological system is out of its normal equilibrium, there is a specific cause to this, and the disequilibrium will not be fixed until the cause is addressed.


That said, I may still experiment with a mifepristone HPA-axis reset, as I've nothing to lose in trying.
On the theoretically level, i don't know, but it seems like people can have abnormal endocrine and hormone levels for years at a time. i guess what you're saying is that it can't be primary, there has to be something sustaining it
 

frozenborderline

Senior Member
Messages
4,405
i watched some of "the science of stress" great courses vid with robert sapolsky which does a good job of breaking down that shit so that a dumbass like me can understand it. He said that scientists are moving toward a different term than homeostasis, which i forget...

but he also made it clear that homeostatic mechanisms can get totally smashed by the environmental consequences of a modern lifestyle. social factors turn on a stress response that is pathological when chronically activated, only adaptive as an acute response to a predator or danger...
so i believe that homeostasis can stay out of whack.
 

Hip

Senior Member
Messages
17,824
i guess what you're saying is that it can't be primary, there has to be something sustaining it

It's hard to explain, but in physics it is known as hysteresis, which means that the current state of a physical system depends not only on the current forces or factors applied to the system, but also on the past recent history of the system.

In a linear system, the system will respond in a linear way to the forces or factors applied to it, and once those forced are removed, the system will always return to its original starting state, it's natural point of equilibrium.

But in a system subject to hysteresis, even when the forces or factors are completely removed, the system may not return to its original starting state, but may remain "stuck" in some other state, because the system can have more that one natural equilibrium point that it settles into.


Some mathematical models of the HPA axis suggest the HPA axis could be a system subject to hysteresis, rather than being a linear system. If true, that means that when a significant factor acts on the HPA axis, once that factor ceases to act and is no longer present, the HPA axis may not settle back into its original starting point of equilibrium, but may remain stuck at some other secondary point of equilibrium. In which case, the HPA axis may not function properly.

So that's the idea of a HPA axis reset: to knock the HPA axis back to its original equilibrium point, so that normal functioning resumes.

But whether those HPA axis mathematical models in which hysteresis is found accurately reflect the real biological functioning of the HPA axis is another question.


But my guess is that if the HPA axis is not functioning from the basis of its natural state of equilibrium, and is instead stuck at some secondary point of equilibrium, there is likely some agency (like infection or autoimmunity) causing and sustaining this abnormal equilibrium, rather than this resulting just from hysteresis. But that's just my guess.
 
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Jesse2233

Senior Member
Messages
1,942
Location
Southern California
But in a system subject to hysteresis, even when the forces or factors are completely removed, the system may not return to its original starting state, but may remain "stuck" in some other state, because the system can have more that one natural equilibrium point that it settles into

Interesting theoretical framework, although I like the idea of a treatable cause better than a self perpetuating loop that you somehow need to knock back to a previous state.

If true, might hysteresis be the result of epigenetic changes from a long gone trigger? And what is it about hysteresis in the context of disease that you think is unlikely?
 

Hip

Senior Member
Messages
17,824
Interesting theoretical framework, although I like the idea of a treatable cause better than a self perpetuating loop that you somehow need to knock back to a previous state.

If true, might hysteresis be the result of epigenetic changes from a long gone trigger? And what is it about hysteresis in the context of disease that you think is unlikely?

Although a self-perpetuating loop might be easier to treat, because in such a scenario, there is nothing wrong with the body, it's just that a system of the body has got stuck in this loop, and just needs to be prodded out of it in order to fall back to normal functioning and health.

And that's the reason I think such self-perpetuating loops are an unlikely scenario to explain diseases, because how many diseases or conditions of the body do you know of which are completely cured by just a prod that pushes the body out of its self-perpetuating loop and back into normality? If only curing diseases were that easy!



The dysfunctions of the HPA axis could conceivably be due to a long gone trigger that leaves a permanent mark in the form of epigenetic changes, but then I think you would say that the dysfunction would not be a due to hysteresis, but due to the agency of the epigenetic change.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
because how many diseases or conditions of the body do you know of which are completely cured by just a prod that pushes the body out of its self-perpetuating loop and back into normality

Excellent point, though I suppose one could start to split hairs on where you draw the line as to what is truly self perpetuating by no other mechanism than its own momentum vs a feedback loop with independent ongoing causes
 

frozenborderline

Senior Member
Messages
4,405
It's hard to explain, but in physics it is known as hysteresis, which means that the current state of a physical system depends not only on the current forces or factors applied to the system, but also on the past recent history of the system.

In a linear system, the system will respond in a linear way to the forces or factors applied to it, and once those forced are removed, the system will always return to its original starting state, it's natural point of equilibrium.

But in a system subject to hysteresis, even when the forces or factors are completely removed, the system may not return to its original starting state, but may remain "stuck" in some other state, because the system can have more that one natural equilibrium point that it settles into.


Some mathematical models of the HPA axis suggest the HPA axis could be a system subject to hysteresis, rather than being a linear system. If true, that means that when a significant factor acts on the HPA axis, once that factor ceases to act and is no longer present, the HPA axis may not settle back into its original starting point of equilibrium, but may remain stuck at some other secondary point of equilibrium. In which case, the HPA axis may not function properly.

So that's the idea of a HPA axis reset: to knock the HPA axis back to its original equilibrium point, so that normal functioning resumes.

But whether those HPA axis mathematical models in which hysteresis is found accurately reflect the real biological functioning of the HPA axis is another question.


But my guess is that if the HPA axis is not functioning from the basis of its natural state of equilibrium, and is instead stuck at some secondary point of equilibrium, there is likely some agency (like infection or autoimmunity) causing and sustaining this abnormal equilibrium, rather than this resulting just from hysteresis. But that's just my guess.
this is totally fascinating, Hip, thanks for the explanation
 

Hip

Senior Member
Messages
17,824
I suppose one could start to split hairs on where you draw the line as to what is truly self perpetuating by no other mechanism than its own momentum vs a feedback loop with independent ongoing causes

Yes, I guess you could split hairs in terms whether things like epigenetics are considered part of your dynamic system (the HPA axis in this case), or are considered a factor external to the system, with epigenetics then being seen as an external adjustment or a calibration to the system.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
@Hip right because some external context has to govern any dynamic biological system doesn’t it?

And if not, then what would be an example of biological hysteresis and a plausible mechanistic basis at a granular level?
 

Forbin

Senior Member
Messages
966
And I don't generally subscribe to the notion that physiology can be throw out of homeostatic equilibrium, and once this happens, it can maintain itself in this out-of-equilibrium state, in a self-sustaining way, until such time as it is reset, which then fixes the problem.

This is obviously in a way different realm than the HPA axis, but abnormal heart rhythms (most dramatically ventricular fibrillation) can be "reset." You could argue that v-fib is not sustainable, but AFib can go on for a long time.
 

Hip

Senior Member
Messages
17,824
This is obviously in a way different realm than the HPA axis, but abnormal heart rhythms (most dramatically ventricular fibrillation) can be "reset." You could argue that v-fib is not sustainable, but AFib can go on for a long time.

Yes, I was thinking about that, as that's the only example I can come up with where a system of the body can fall into an abnormal equilibrium point that causes dysfunction, and were a nudge of the system (in a form of an electric shock to the heart) kicks the system back into its normal equilibrium, where normal functioning resumes.

I seem to remember that chaos theory has been used to mathematically model the heartbeat, and chaos theory is similar to hysteresis in that it can involve multiple equilibrium points ("attractors" as they call them in chaos theory) which the system can fall into.

Although I am not sure if anyone has mathematically modeled heart fibrillation in terms of the system falling into an undesirable attractor point.



And if not, then what would be an example of biological hysteresis and a plausible mechanistic basis at a granular level?

Generally speaking, I would not think there will be many system in the body that have multiple equilibrium points that they can get "stuck" in, because this would cause inconsistent behavior of a system, and that's not something you would want in biology. Presumably nature (evolution) would tend to create reliable biological systems that behave in a consistent manner.
 
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wastwater

Senior Member
Messages
1,271
Location
uk
I just came across this in my FOXC1 gene paper posted under chromosome 6 it may activate FOXC1 gene and FOXO1A
NK cell function is probably a downstream effect
Foxo stimulators Tetrahydrocurcumin
Anthocyanin rich purple wheat
Mifepristone sent heat shock protein 70 through the roof as I’m probably missing this gene I presume my hsp-70 is low
G protein receptor 39 and zinc
Col4a3 mentioned
 
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Isaiah 58:11

Senior Member
Messages
116
Location
A Sun-Scorched Land
Yes, I was thinking about that, as that's the only example I can come up with where a system of the body can fall into an abnormal equilibrium point that causes dysfunction, and were a nudge of the system (in a form of an electric shock to the heart) kicks the system back into its normal equilibrium, where normal functioning resumes.

I just experienced a system reset of sorts that had me wondering about all of this. I was put on propanalol for POTS and after about a month I had a day where I forgot to take it. I noticed that my heart rate was normal, which seemed odd for something that is dosed throughout the day, so I just kept not taking it out of curiosity. My heart rate stayed totally normal (mid 60s) for about a month and is just starting to creep up again (80s, but not 100-120 at rest where it was). The propanalol seemed to actually reset something that with continued illness is gradually coming undone again. (And, yes, I am going to restart the Propanalol now.)

Anyway, I now believe it is possible drugs like mifepristone can actually reset things and I am curious to see if the results are permanent or if the dysfunction returns gradually and the medication must be taken periodically.
 

wastwater

Senior Member
Messages
1,271
Location
uk
Mifepristone was trialled for psychotic depression and seemed to work,shame it never made it to market