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Glucorticoids and Stress

Discussion in 'General ME/CFS Discussion' started by msf, Mar 3, 2016.

  1. msf

    msf Senior Member

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    I haven´t read that much about hormonal/adrenal issues in ME, since it seems both very complex and also a secondary, rather than primary cause of symptoms. So I would appreciate any views on how relevant the issues discussed in the following video are to ME:



    It´s a long video, but I was only about ten minutes in when it started to sound rather familiar...If it isn´t relevant to ME then no matter, it´s a fascinating talk anyway!
     
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  2. JaimeS

    JaimeS Senior Member

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    Thanks for sharing this, @msf ! Thoughts (and summary for ppl with attention issues that won't stand up to 1 hr 10 min):

    As discussed elsewhere, my glucocorticoids are low and need to stay low for me to feel healthy. I feel like this is a chicken-or-egg question according to the speaker, though. He outright says that the effects of anything that damages the brain are magnified in the presence of glucocorticoids; so it doesn't rule out pathogenicity or ischemia or ROS damage, it just postulates the connection between GC and increased damage.

    The GC-mediated damage appears to be induced by an "energy crisis" in the neuron. A study showed that:
    • Damaging stimulus causes X neuronal damage
    • Damaging stimulus plus GC causes dose-dependent X(Y) damage
    • Damaging stimulus plus GC plus an energy source (mannose, which has its own brain transport system) dramatically decreases damage (Hard to see diagram, but it looks like barely higher than X damage)
    • Fructose doesn't get into the brain, but ketones seem to work more or less as mannose does
    Glucocorticoids inhibit glucose uptake. An increased sensitivity to glucocorticoids (and adverse reactions) has been documented in PWME, along with a corresponding generally increased circulating blood glucose. Except glucocorticoids aren't *supposed* to inhibit glucose uptake in the muscle.

    But what if, in PWME, they do? What if that's the problem: that because of some kind of quirk of genetics, or epigenetic switch, the glucocorticoids that normally prevent glucose from going anywhere but the muscle also block it from the muscle?

    The process he's describing -- by which glucose transporters are yanked off the cell's surface -- could just as easily happen in muscle cells as neurons, presumably.

    Another idea: stripping glucocorticoid receptors from muscle cells could be a protective measure to give all available sugars to the damaged neurons, instead, as they are calling for more energy than usual.

    I find it fascinating that, after a specific point, glucocorticoids become pro-inflammatory. Beyond a simple 'exhaustion-phase' rhetoric, may potentially help to explain why the body stops producing them after a phase of high corticoids: they are damaging. This may or may not be part of the mechanism that causes the body to decrease production.

    I also like the reminder that receptors are simply chemicals that can suffer from oxidative damage; biology and chemistry are taught so differently and with such a gap between them that even after having taught both, I find myself re-absorbing that biological structures are simply made of chemicals, constantly! :)


    Now, let's get to the good stuff. What to do:

    1. Block glucocorticoid receptors -- liquorice, anyone? Though that has some ADH fx as well.
    2. Block glucocorticoid production -- my body tries for this anyhow by drastically decreasing ADH; he mentions RU-486, which I think is the morning after pill... he states that it blocks the progesterone receptor.
    3. Supplement with mannose and/or ketones; I would add the ketogenic diet, also...
    4. "Build a better neuron" with gene therapy.

    Gene Therapy:

    You could find a way to overexpress the glucose transporter in some neurons! Get more glucose into the brain that way. This will reduce glutamate excitotoxicity.

    Unfortunately, the therapeutic window is short: four hours before the effect of gene therapy is negligible. So the research team faced the difficulty of what to do for longer-term stressors as opposed to dramatic incidences of brain damage like head trauma or stroke.

    We all know that there are some pathogens that are opportunistic and give us flare-ups with increased stress. Pathogens like herpes virus actually have GREs all over them. (No, not questions about two trains heading in the opposite direction at different speeds: glucocorticoid responsive elements.) In other words, encountering increased glucocorticoids causes them to 'switch on'. Using herpes virus as a starting point, the team was able to create a gene therapy that was stress-inducible. It also 'switches on' when you are stressed, so that glucose transporters rev up ONLY in the presence of increased glucocorticoids.

    Since estrogen has positive effects neuronally, the research team produced an estrogen/GC receptor chimera (a combo of the two).
    • The glucocorticoid's hormone-binding domain
    • The estrogen's DNA-binding domain
    So you have an estrogen response instead of a glucocorticoid response, which is neuroprotective.

    This is all in the hippocamus; if you do this in the amygdala, you reduce anxiety and fear...

    "You can't psychologically re-frame... and grow from this experience...." (In reference to being unexpectedly gored by an elephant.) :rolleyes::D:rofl: He goes on to describe any pathogen, brain trauma and so on as being uncontrollable.

    As someone who's never had particularly high blood pressure, high glucocorticoids, low HDL, or reduced IGF-1 (and I have had all of these checked!) I'm not sure ME patients fit the low-dominance model of stress. So moving on....

    But it is interesting. Glucocorticoid levels are affected by:
    1. If you can tell the difference between a threat and not.
    2. If you have an outlet for after everyday stress (with others), rather than 'dealing' alone
    3. In a socially stressful event, are you aware of resolution?
     
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  3. msf

    msf Senior Member

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    Great summary, JaimeS! I don´t know if I didn´t have the will, the energy or the ability to summarise it myself, perhaps Sapolsky could tell me which it is! The bit that made me think about ME was when he started talking about how glucorticoids enable neuron damage in an energy-deficient state.

    Re: low glucorticoids, perhaps this is another example of immune exhaustion. I noted that the damage can occur in a very short period of time, at least in cases such as stroke.

    This seems like a good summary of the general issues: http://phoenixrising.me/research-2/...gue-syndrome-mecfs-artifact-or-central-factor

    The bit about hypocortolism being protective makes a lot of sense to me.
     
  4. JaimeS

    JaimeS Senior Member

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    To be clear, this was my supposition and not his. :)

    I'm really glad you brought this here, @msf -- it was fascinating and I feel like I understand GC far better than before. :D

    -J
     
  5. msf

    msf Senior Member

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    It was also the supposition of whoever wrote that PR article I posted.

    I´m really glad I found out about this guy, he reminds me a lot of Stephen Pinker. And I have the Joe Rogan podcast to thank for it! He hasn´t been on it, but one of the guests mentioned his work.
     
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