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haidut

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I made a few posts recently discussing the blocking effects of pregnenolone on TLR4 and TLR family receptors in general, and the reduction of systemic inflammation stemming from this blockade/regulation.
https://raypeatforum.com/community/threads/pregnenolone-is-a-potent-functional-endotoxin-tlr4-antagonist.27846/
It is well-known that glucocorticoids and mineralocorticoids are protective against endotoxemic shock, possibly due to blocking the hypotensive and inflammatory effects of endotoxin. However, a specific mechanism of action for the protective effects of steroids has still not been officially proposed, aside from the TLR4 antagonism by pregnenolone above.
The study below is really interesting because not only does it show that a HED 1mg/kg progesterone was remarkably protective against endotoxin inflammation and lethality, but it also suggests that progesterone may react directly with endotoxin and form a covalent bond. This progesterone-endotoxin complex is apparently inactive, which suggests that a significant portion of progesterone's (and likely pregnenolone's) protective effects against endotoxin may stem from a direct deactivation effects. If true, it would put steroids like pregnenolone/progesterone on par with charcoal as there are very few other known direct binders/deactivators of endotoxin. This effect is on top of the TLR4/histamine/serotonin/prostaglandin/etc antagonism that these steroids are already known to possess, and suggests that it is the physical properties of C-21 steroids rather than their "receptor" effects that may be responsible for some of their benefits. Truly remarkable, and similar to the rationale Peat provided for glycine's benefits, which cannot be explained by its genomic or enzymatic interactions.

The effect of progesterone on cats administered endotoxin. - PubMed - NCBI
"...We have found that progesterone markedly prolongs survival in cats that have been given endotoxin. The effect of progesterone on the course of endotoxic shock varied with the time the progesterone was given. Progesterone incubated with or given simultaneously with endotoxin lessened the initial and secondary fall in blood pressure seen in the control animals. Progesterone given 5 or 30 minutes after the endotoxin restored the initial falling blood pressure to near-normal levels and lessened the secondary hypotension which occurred at 1 to 1% hours in the control animals. The mechanism responsible for the initial hypotensive episode following the administration of endotoxin is thought to be related to the liberation of histamine or a similar vasoactive substance [3, 5]."

"...The preliminary results of our work with the ether and aqueous extracts of progesterone and endotoxin, and the increased survival obtained with prior incubation of endotoxin with progesterone, appear to indicate that progesterone may form an in vitro bond with the endotoxin compound. This has been suggested as a possible alternate explanation of the action of aldosterone and endotoxin [3, 4]. Whether this results in direct inhibition of the endotoxin or the inhibition is mediated through unknown substances in vivo is pure conjecture at this time. DeSaulles has demonstrated increased survival in animals given endotoxin and 19 oxoprogesterone [1]. This compound reportedly has no antiinflammatory or mineralcorticoid effects and may indicate that the inhibition of endotoxin by the glucocorticoids, mineralcorticoids, and progesterone bears no relationship to their known physiological actions."
 
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That’s incredible.

I think everyone should learn to recognize the feeling of too much endotoxin. I recognize it as a certain pattern of body awareness and sometimes body aches that feel like a very light flu.
 

haidut

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That’s incredible.

I think everyone should learn to recognize the feeling of too much endotoxin. I recognize it as a certain pattern of body awareness and sometimes body aches that feel like a very light flu.

I agree. In my case, it manifests mostly as low back ache, joint pain and a vague feeling of malaise. All of these symptoms exacerbate quite a bit if drinking more than 3 beers when going out, which is not surprising as alcohol is itself TLR4 agonist, 5-HT3 agonist and if that was not enough it also enhanced absorption of endotoxin from intestine into the blood.
 

haidut

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@haidut do you think it's more effective to ingest progesterone or apply it transdermally?

I think both methods work well, but the transdermal progesterone tends to raise allopregnanolone more as the skin has high expression of 5-AR and 3a-HSD. I personally like progesterone orally when it is dissolved in tocopherol/MCT and topically when it is in an ethanol-based solvent such as our SFA/ethanol mix.
 

Risingfire

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I think both methods work well, but the transdermal progesterone tends to raise allopregnanolone more as the skin has high expression of 5-AR and 3a-HSD. I personally like progesterone orally when it is dissolved in tocopherol/MCT and topically when it is in an ethanol-based solvent such as our SFA/ethanol mix.
Thank you!
 

shine

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My digestion has been pretty bad and slow lately and I've noticed that my usual 45-50mg dose of oral pregnenolone doesn't give me the same effect that it used to. Maybe a good amount of it is being used to counteract the endotoxin in the gut.
Interestingly, sublingual and topical preg still gives me the same mood-lifting and cognition enhancing effects that I've experienced from the oral route.
 

yerrag

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That’s incredible.

I think everyone should learn to recognize the feeling of too much endotoxin. I recognize it as a certain pattern of body awareness and sometimes body aches that feel like a very light flu.

I've been having this left hip soreness that came about 2 weeks ago and never went away. Now I think it is LPS-related as I come to realize that LPS is being released as my intake of doxycycline, and my topical application of turpentine, has been killing the bacteria slowly being released from the lysing of my artherosclerotic plaque with proteolytic enzymes. I should use go back to applying progesterone although an HED dose of 1 mg/kg seems rather high for me as that would come out to 70mg/day for me. I have to check on my notes the time I applied progesterone in excess causing my temps to warm up to 38C and I had the chills that evening.
 

yerrag

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On another note, it makes me wonder about BPH, where I'm told that increased urination is a sign of BPH. Is it possible that it's merely the result of low progesterone not being able to deactivate endotoxin? I'm getting to think from my recent experience with increased urination that it really had to do with having an LPS storm form bacteria being killed (bacteria being activated/released from its dormant state as plaque is being lysed). I think that a cause of increased urination may be from having increased LPS production from bacteria die-off. Progesterone would help in this case then.
 
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On another note, it makes me wonder about BPH, where I'm told that increased urination is a sign of BPH. Is it possible that it's merely the result of low progesterone not being able to deactivate endotoxin? I'm getting to think from my recent experience with increased urination that it really had to do with having an LPS storm form bacteria being killed (bacteria being activated/released from its dormant state as plaque is being lysed). I think that a cause of increased urination may be from having increased LPS production from bacteria die-off. Progesterone would help in this case then.

Haidut told me that BPH is from endotoxin. I must agree. Yes progesterone and pregnenolone and DHEA are helpful. As is aspirin.
 

yerrag

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Haidut told me that BPH is from endotoxin. I must agree. Yes progesterone and pregnenolone and DHEA are helpful. As is aspirin.
Thanks. LPS and Progesterone (perhaps pregnenolone/DHEA) to deal with it just may be the final key to unlocking my the mystery behind my high blood pressure. Will see how the coming weeks and months turn out. The effect of an LPS storm on my urination frequency was the clue. I just applied 30mg progesterone and I'll know when I wake up if it's been effective. Thanks!
 

yerrag

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I think I slept better, but my heart rate went down to 58 from 67 two hours after the topical progesterone. Perhaps due more to the inotropic/lusitropic effect of progesterone than to lowered metabolism.

But the most telling effect is that my left hip joint pain is gone. This arthritic pain came about after I got into using proteolytic enzymes to lyse away plaque. I believe that it was the LPS that caused the pain, as use of doxycycline did not fix it. This leads me to believe it was not the bacterial component but the LPS component that brought about the hip joint pain. My 30mg dose of progesterone (Progestene) did the job!

What other substances bind and deactivate LPS? I understand vit A, vit D, B2, B3, emodin, as well as cyproheptadine can block TLR4, but the effect of binding/deactivating would be better I think.

Binding would lead to the LPS being excreted through urine or through the fecal route, wouldn't it?
 
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Soren

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Anyone have any thought on an appropriate dose to lower endotoxin?
 

Jam

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What other substances bind and deactivate LPS? I understand vit A, vit D, B2, B3, emodin, as well as cyproheptadine can block TLR4, but the effect of binding/deactivating would be better I think.

It seems that cholesterol (specifically LDL) is one of the body's most powerful defenses against endotoxin.

High cholesterol may protect against infections and atherosclerosis
Lipopolysaccharide, or endotoxin, the main pathogenic factor of Gram-negative bacteria, binds rapidly to lipoproteins,6 mainly LDL,7 and lipoprotein-bound endotoxin is unable to activate the secretion of various cytokines by monocytes in vitro.6,7,10

Have you tested your LDL levels recently?
 
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