Haidut Vs Peat? Cortisone / Cortisol Defficiency (?) And Autoimmunity

judi

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Hello

Sorry about the provocative title of this thread - I'm not getting many views or answers on my original thread here:
Bioenergetic View Of Autoimmunity: Struggling To Understand Cortisol's Action

To reiterate, after listening to Haidut talking to Danny Roddy in A Bioenergetic View Of Autoimmunity [Generative Energy #12] I was questioning how cortisol could be in excess in "autoimmune" conditions (leading to tissue breakdown and inflammation and subsequent immune system's over-reaction), but supplemental hydrocortisone / prednisone etc. would be able to relieve the symptoms of inflammation and pain (please see the original thread for more details).

I haven't been able to explain the mechanism.

It seems to me that the more logical explanation could be an inability of the body to produce sufficient cortisone in the presence of hypothyroidism, leading to chronic inflammation, which would then explain the symptom relief after supplementation of physiological dose of steroids.

Please see this quotation from Ray Peat's article Blocking Tissue Destruction:
· While normal thyroid function is required for the secretion of the adrenal hormones, the basic signal which causes cortisone to be formed is a drop in the blood glucose level. The increased energy requirement of any stress tends to cause the blood sugar to fall slightly, but hypothyroidism itself tends to depress blood sugar.

· The person with low thyroid function is more likely than a normal person to require cortisone to cope with a certain amount of stress. However, if large amounts of cortisone are produced for a long time, the toxic effects of the hormone begin to appear. According to Meerson, heart attacks are provoked and aggravated by the cortisone produced during stress. (Meerson and his colleagues have demonstrated that the progress of a heart attack can be halted by a treatment including natural substances such as vitamin E and magnesium.)

· While hypothyroidism makes the body require more cortisone to sustain blood sugar and energy production, it also limits the ability to produce cortisone, so in some cases stress produces symptoms resulting from a deficiency of cortisone, including various forms of arthritis and more generalized types of chronic inflammation.

· Often, a small physiological dose of natural hydrocortisone can help the patient meet the stress, without causing harmful side-effects. While treating the symptoms with cortisone for a short time, it is important to try to learn the basic cause of the problem, by checking for hypothyroidism, vitamin A deficiency, protein deficiency, a lack of sunlight, etc. (I suspect that light on the skin directly increases the skin's production of steroids, without depending on other organs. Different steroids probably involve different frequencies of light, but orange and red light seem to be important frequencies.) Using cortisone in this way, physiologically rather than pharmacologically, it is not likely to cause the serious problems mentioned above.

· Stress-induced cortisone deficiency is thought to be a factor in a great variety of unpleasant conditions, from allergies to ulcerative colitis, and in many forms of arthritis. The stress which can cause a cortisone deficiency is even more likely to disturb formation of progesterone and thyroid hormone, so the fact that cortisone can relieve symptoms does not mean that it has corrected the problem.

· According to the Physicians' Desk Referenc, hormones similar to cortisone are useful for treating rheumatoid arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, acute gouty arthritis, acute nonspecific tenosynovitis, psoriatic arthritis, ankylosing spondylitis, acute and subacute bursitis, and epicondylitis.

· Although cortisone supplementation can help in a great variety of stress-related diseases, no curewill take place unless the basic cause is discovered. Besides the thyroid, the other class of adaptive hormones which are often out of balance in the diseases of stress, is the group of hormones produced mainly by the gonads: the "reproductive hormones." During pregnancy these hormones serve to protect the developing baby from the stresses suffered by the mother, but the same hormones function as part to the protective anti-stress system in the non-pregnant individual, though at a lower level.

· Some forms of arthritis are known to improve or even to disappear during pregnancy. As mentioned above, the hormones of pregnancy can make up for a lack of adrenal cortex hormones. During a healthy pregnancy, many hormones are present in increased amounts, including the thyroid hormones. Progesterone, which is the most abundant hormone of pregnancy, has both anti-inflammatory and anesthetic actions, which would be of obvious benefit in arthritis.

Real life example: After prolonged stress at work, my friend has developed what seems like rheumatic arthritis or soft tissue rheumatism, was prescribed 5mg prednisolone daily, took that for 3 weeks and experienced symptom relief. Now off prednisolone her condition has worsened. (Confounding variable= cholesterol of 150 mg/dl (4.0 mmol/l))

I would be grateful for any explanations/opinions.

Thank you
Judi
 

Blossom

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Hi Judi,

I believe haidut and Danny were talking about chronic unrelenting elevated cortisol wrecking the body over time (I haven’t listened though so hopefully I’m not misrepresenting them). People get caught in a viscous stress cycle that can be hard to break and the body secretes more and more cortisol but that then results in increasing tissue damage- more damage, more cortisol, more damage, more cortisol....
Prednisone completely shuts down our bodies production of cortisol, is much stronger than what our body secretes and has an immediate anti inflammatory effect. If you look at any long term prednisone user though you will see tissue atrophy as one of many side effects.
It is impossible to know for certain what is going on with your coworker unless she gets tested. Pregnenolone is one thing that might be useful to research for her situation.
I hope you get a more scientific explanation at some point!
 

rob

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@judi Sorry you didn't get more responses; I hope others get back.

In the meantime, I feel my reply to your last post was lost in translation a bit in some areas – my fault. So I'll try again and expand.

By the way, having gone through similar things on the stress front with my Crohn's - which shares the same immune steering as RA - your friend has my sincerest sympathies.

Also, this is all theory and it does depend a bit on what you consider the disease etiology.

Anyway, here are some ideas:

1) The stress your friend was experiencing would have pushed up cortisol within physiologic limits. This would compromise her immune response, explicitly it would have somewhat lowered – not abolished –lymphocyte levels. Of course, if prolonged, this would have set the stage for infections – some theories implicate pathogens in the etiology of RA and other autoimmune diseases – and an inflammatory response.

Once inflammation has begun, corticosteroid therapy essentially provides supranormal levels of cortisol (can be 10 times plus physiologic levels). At this amount, you get much higher levels of immune suppression than you would with the ordinary production of cortisol. Consequently, immune reponse is knocked right down – not just lowered – and the patient begins to feel better. As explained before, the problem is, long term, this isn't doing anything to help treat the root of the disease, in this case lingering pathogens.

2) This is more theoretical but interesting to consider, psychological stress causes the brain to produce corticotrophin-releasing hormone (CRH). CRH has been shown to provoke inflammatory pathways via mast cell activation. For example, in the study Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor it's stated: "CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress". Indeed, in RA there seem to be a large number of mast cells in the synovium (see Synovial mast cells: role in acute and chronic arthritis. - PubMed - NCBI). Since human mast cells have been shown to have CRH receptors, I wouldn't be surprised if stress caused RA issues in such a manner.

As said before, and again this is theoretical, I imagine corticosteroid therapy bypasses CRH production because the brain isn't registering a stressful event to produce the cortisol. Moreover, because cortisol levels, via negative feedback, lower CRH levels, such therapy might actually work to suppress CRH production in the first place, thus, inhibiting the mast-cell mediated mechansim detailed above. Hence the differential effect of stress and hydrocortisone/prednisolone.

3) This study (Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk) indicated that stress could lead to glucocorticoid recepor resistance/insensitivity (GCR). In models of GCR, cortisol cannot properly regulate immune cells activity in certain tissues and an overactive immune response results. Again, a bit like idea 1, supranormal levels of cortisol via hydrocortisone/prednisolone could overcome this resistance/insensitivity as it's not an absolute resistance. By this theory, the steroid therapy would then provide the chemical messages to properly regulate the immune response.

Other than that, what I am sure of is that stress – anxiety and overexcitement – and, in general, excessive SNS activity is health monster that I think we're only starting to stratch the surface of. Moving forwards, I hope your friend can find ways to, mentally, make life a softer, kinder place to land.
 
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haidut

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Hello

Sorry about the provocative title of this thread - I'm not getting many views or answers on my original thread here:
Bioenergetic View Of Autoimmunity: Struggling To Understand Cortisol's Action

To reiterate, after listening to Haidut talking to Danny Roddy in A Bioenergetic View Of Autoimmunity [Generative Energy #12] I was questioning how cortisol could be in excess in "autoimmune" conditions (leading to tissue breakdown and inflammation and subsequent immune system's over-reaction), but supplemental hydrocortisone / prednisone etc. would be able to relieve the symptoms of inflammation and pain (please see the original thread for more details).

I haven't been able to explain the mechanism.

It seems to me that the more logical explanation could be an inability of the body to produce sufficient cortisone in the presence of hypothyroidism, leading to chronic inflammation, which would then explain the symptom relief after supplementation of physiological dose of steroids.

Please see this quotation from Ray Peat's article Blocking Tissue Destruction:


Real life example: After prolonged stress at work, my friend has developed what seems like rheumatic arthritis or soft tissue rheumatism, was prescribed 5mg prednisolone daily, took that for 3 weeks and experienced symptom relief. Now off prednisolone her condition has worsened. (Confounding variable= cholesterol of 150 mg/dl (4.0 mmol/l))

I would be grateful for any explanations/opinions.

Thank you
Judi

In addition to the comments other people provided, we also discussed the role of CRF in autoimmune conditions. Not sure if that discussion made it into the final cut but CRF is the starting point of the stress cascade and despite cortisol being anti-inflammatory, CRF is pro-inflammatory. So, it is quite possible to have elevated cortisol and still high inflammation due to elevated CRF. In this situation, you get both the inflammation due to CRF and tissue destruction due to cortisol. Cortisol's anti-inflammatory effects cannot block the pro-inflammatory ones of CRF as those are direct and specific to a CRF "receptor". However, pregnenolone, being a CRF antagonist may, and this is probably a major pathway through which pregnenolone helped autoimmune conditions such as RA back in the first half of the 20th century. Unsurprisingly, CRF has been implicated in at least one autoimmune condition (e.g. MS) and I am surprised it is not being investigated as a possible causative factor in other ones such as RA, IBD, psoriasis, Lupus, etc.
Corticotropin-releasing hormone - Wikipedia
"...In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention. Although the distal action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten inflammation, a process being investigated in multiple sclerosis research.[8]"
Pregnenolone Is The Most Potent Inhibitor Of The Stress Signal (CRH)

Finally, keep in mind that chronic usage of exogenous cortisol can lead to the GR getting downregulated in the hypothalamus and as such the negative feedback which cortisol exerts on CRF to abate. Thus, a person would end up with high CRF, high cortisol (through administration) and suppressed adrenal function - without a doubt a pretty bad place to be. In situations like that, CRF antagonists are probably the only way out, yet doctors keep prescribing cortisol until the person becomes Cushingoid and may even die due to PML as a result of the immunosuppression from cortisol.
Progressive multifocal leukoencephalopathy - Wikipedia

@Blossom @rob
 

rob

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@haidut As per my second point above, mast cells seem to mediate CRH/CRF’s pro-inflammatory effect in peripheral tissue.

Therefore, another possibility, alongside your suggestion of CRH-R1 antagonists, would be mast cell stabilisers.

On pregnenolone, one interesting caveat to consider is the counterintuitive effect GABAA receptor positive allosteric modulators, such as allopregnenolone, may have on a subject when under stress.

In brief, there are indications that stress can cause dephosphorylation of the KCC2 co-transporter resulting in the collapse of the chloride gradient. Consequently, GABA agonists end up causing depolarisation of GABAergic neurons, thus potentiating the stress response and elevating CRH.

Here’s a couple of quick references:
The reciprocal regulation of stress hormones and GABAA receptors
Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility

As for:
...I am surprised it is not being investigated as a possible causative factor in other ones such as RA, IBD, psoriasis, Lupus, etc.

It is, but progress on the neurogenic side of things seems annoyingly slow – as ever.

@judi It's also worth noting that the steroid hormones (prognenolone, progesterone, cortisol, estradiol, aldosterone etc.) are synthesised within cells' mitochondria. Here's a good overview of all of this from a stress perspective: https://www.sciencedirect.com/science/article/pii/S0091302218300062

There are numerous ways mitochondrial dysfunction can be implicated in diseases like RA, so a diet/supplement regime that supports cells bioenergetically is worth exploring. Personally, I have had great success with nicotinamide riboside – an interesting form of vitamin B3 – in managing my Crohn's disease. Don't know if it will translate to your friend's RA but another possibility to look into.
 
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judi

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Thank you so much @haidut, @rob and @Blossom for your replies.

@haidut - no, the CRF/CRH discussion never made it into your Autoimmunity podcast.

But maybe the CRF/CRH is the missing piece of the puzzle then? Would you please review this scenario and see if it looks reasonably complete? I'm still seeking a couple of clarifications at the end (see bold font, plz).

Continuous stress raises secretion of stress hormones like CRF/CRH and cortisol, which leads to tissue breakdown and suppression of the immune system. Cortisol acts as an anti-inflammatory (due to inhibiting effect on pro-inflammatory enzymes of white blood cells, histamine, prostaglandins & leukotrienes) but inflammation is still present due to the CRF/CRH action. CRF/CRH is being presumably being produced because the body is crying for more cortisol and/or because the existing elevated estrogen is disrupting the negative feedback system signaling.

Due to the immunosuppressive action of cortisol (reduction of the number and activity of white blood cells), opportunistic pathogens may take up residence.

So here we have:

Breakdown of tissue, continuing low grade inflammation due to CRF/CRH and possibly opportunistic infection, increasing debris due to suppressed immune system.

After this scenario continues for a prolonged period and while the amount of debris increases over time, cortisol isn't being produced in sufficient quantities (especially in the presence of hypothyroidism) but presumably the secretion of CRF/CRH is cranked up, contributing to the continuing inflammation, which leads to the overactivity of the immune system and production of antibodies….

Here is where a person gets diagnosed with an autoimmune condition and given corticosteroids.


Now here is where things get a bit blurry for me again:

Exogenous corticosteroids in large quantities would presumably switch off the CRF/CRH secretion, so the CRF/CRH-mediated inflammation would stop….. So now the patient feels better due to calming of the inflammation but suffers continuous tissue breakdown, suppressed immune system and possibly opportunistic pathogenic activity.

What is preventing septicemia here? Or is it just a question of time?

Also - upon administration of exogenous corticosteroids CRF/CRH secretion is switched off….. but presumably the elevated estrogen disrupting the negative feedback system signaling is still present, so why wouldn't the CRF/CRH secretion continue unabated?

Over time the GR downregulation leads to increasing inflammation due to CRF/CRH renewed secretion in the presence of high cortisol and suppressed immune system = bad news.

Is there anything major missing here?

Thank you very much
Judi
 

rob

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@judi On sepsis, yes, there’s a definite risk... Septic arthritis in patients with rheumatoid arthritis

“There is an increasing number of rheumatoid patients who get septic arthritis. Chronic use of steroids is one of the important predisposing factors.”

The same study also notes a general increased risk of infection in the RA population. Again, the combination of poorly regulated CRH and its downstream mast cell mediated effects plus the immunosuppressive actions of glucocorticoids could go some of the way in explaining this.

As I concluded about my Crohn’s last year, and might pertain to your friend’s case, I think it’s a mixture of neurogenic and bioenergetic factors (tissue-specific mitochondrial dysfunction factoring in genetic predisposition), ultimately, leading to physiologic stressors that internal resources cannot meet. So, manage the stress through multiple means (maybe explore CRH
-R1 antagonists and mast cell stabilisers) and, as is routinely discussed on this forum, optimise metabolism (check thyroid and look into things that improve cellular respiration).

If any pathogen is intracellular then supporting the mitochondria is very important as they’re vital apparatus in coordinating an effective cellular response.

Generally, I think it’s no surprise that mitochondria-targeted antioxidants, such as mitoq and skq1, have proven very effective in autoimmune models e.g. Efficacy of Mitochondrial Antioxidant Plastoquinonyl-decyl-triphenylphosphonium Bromide (SkQ1) in the Rat Model of Autoimmune Arthritis
 
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charlie

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Personally, I have had great success with nicotinamide riboside – an interesting form of vitamin B3 – in managing my Crohn's disease.
How much are you taking?
 

rob

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How much are you taking?

I got things under control with around 1g a day - from the data I’ve seen benefits tend to cap at this amount. Added some TMG since to support methylation as per Chris Masterjohn's logic.

Don't know if it has been cited on here before, but one study that got me interested in NAD+ and autoimmunity was this NAD + protects against EAE by regulating CD4 + T-cell differentiation | Nature Communications.

The study explained that NAD+ upregulation supports Th1 and Th17 differentiation – normally a bad thing in the likes of MS, RA and Crohn's – however, intriguingly, IL-10 and TGF-β1 production were strongly expressed in the lineages, producing net anti-inflammatory benefit.

It also clarrified matters over FK866, a NAMPT enzyme inhibitor that was shown to be beneficial to autoimmune diseases via NAD+ depletion. The study stated that NAD+ depletion led to all round immunosuppression – by essentially starving the immune system of fuel – whereas NAD+ upregulation led to immune system homeostasis through, basically, a more balanced cytokine milieu.

Btw, I'm aware that standard B3 is widely promoted on these forums but NR is significantly more potent in replenishing NAD+ stores. To that end, NR seems a safe and particularly quick way of identifying whether one's system has a deficieny in that direction.

@judi Check out @Sativa's discussion of palmitoylethanolamide (PEA). PEA is a mast cell stabiliser and potent anti-inflammatory, working via the endocannabinoid system – also looks like it upregulates allopregnanolone production. Has some very joint pain specific benefits that are worth chceking out.
 
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