haidut

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I just posted the thread on the anti-cortisol mechanism of pregnenolone.
The Anti-cortisol Mechanism Of Pregnenolone

As I mentioned in that thread, the Peat has been saying that both pregnenolone and progsterone have anti-cortisol effects, however people have been questioning those statements due to both steroids being precursors to the glucocorticoids and aldosterone.
Well, the studies below show that the anti-cortisol mechanism of progesterone is similar to its anti-estrogen one - i.e. it speeds up the dissociation of cortisol from the glucocorticoid receptor (GR), which renders cortisol inactive. In additionm progesterone reduces ACTH release, which also leads to lower cortisol synthesis. Apparently, the anti-cortisol effects of progesterone are well-known in research circles and it is regarded on par with chemicals like pregnenolone-16alpha-carbonitrile (PCN), which is the de-facto standard for GR antagonism in both in vitro and in vivo studies.
As if this GR antagonism was not enough, the last study in the list below shows that progesterone is also an inhibitor of 11b-HSD1 similar to chemicals like emodin. As such, it also directly inhibits cortisol synthesis at a concentration of about 2 uM/L, which is achievable with a 8mg-10mg dosage in most humans. There aren't any other chemicals out there that I know of that can both block cortisol at the receptor level and inhibit its synthesis.

Drug insight: selective agonists and antagonists of the glucocorticoid receptor. - PubMed - NCBI
"...Prednisolone, dexamethasone, and cortisol are all glucocorticoid receptor agonists, progesterone is a glucocorticoid receptor antagonist, and aldosterone has a hemiketyl group on C11, which renders it resistant to the action of 11β- hydroxysteroid dehydrogenase 2, enabling aldosterone to evade the action of this enzyme and gain access to the mineralocorticoid receptor in the renal tubule. RU486 was initially introduced as a progesterone receptor antagonist, but the drug is also a potent glucocorticoid receptor antagonist for some actions and a weak agonist for others. It is the prototypic partial glucocorticoid receptor agonist but lacks anti-inflammatory activity. RU24858 was more recently described and, in vitro, showed promising dissociation between preserved anti-inflammatory activity and lost metabolic activity. The key structural changes in both RU compounds relate, again, to the steroid D-ring and C17."

"...Cortisol binds both the glucocorticoid receptor and the mineralo corticoid receptor; progesterone binds both the progesterone receptor and the glucocorticoid receptor, for which it is an antagonist."

http://www.jbc.org/content/259/3/2007.full.pdf
"...Cultured hepatocytes were incubated in control medium for 72 h and then transferred to medium containing one of the following: dexamethasone (DEX) (lo-@ M); the antiglucocorticoids progesterone (PROG), a-methyltestosterone (aMT), or PCN (all M); a combination of dexamethasone plus an antiglucocorticoid."

"...For example, treatment of hepatocytes with two optimal glucocorticoid agonists gave additive rather than optimal induction of P45opCN (Fig. 5B). Moreover, combined administration of a glucocorticoid agonist plus an antiglucocorticoid (PCN, a-methyltestosterone, and progesterone) blocked induction of tyrosine aminotransferase but failed to inhibit (or actually enhanced) induction of P450pCN."

"...In cultures exposed to dexamethasone (lo-” M) plus a 1000 times excess of a glucocorticoid antagonist, a-methyltestosterone, or progesterone, or PCN the rate of tyrosine aminotransferase synthesis was reduced (23 to 60%) as compared to the rate in cultures receiving dexamethasone alone (Fig. 3)"


Effects of adrenocortical and gonadal steroids on the secretion in vitro of corticotrophin and its hypothalamic releasing factor. - PubMed - NCBI
"...The effects of adrenocortical and gonadal steroids on the secretion in vitro of ACTH by adenohypophysial segments and corticotrophin releasing factor (CRF) by isolated hypothalami were studied in the rat. Corticosterone (1.25 X 10(-6) mol/l), betamethasone (2.5 X 10(-8) mol/l) and progesterone (2.5 X 10(-7) mol/l) reduced the hypothalamic extract-induced secretion of ACTH by pituitary tissue in vitro but aldosterone (2 X 10(-7) mol/l), testosterone, androsterone, androstenedione (2 x 10(-7) mol/l), oestradiol, oestriol, and oestrone (10(-6) mol/l) did not."

Progestin-induced enhancement of dexamethasone dissociation from glucocorticoid hormone receptors. - PubMed - NCBI
"...Several groups have reported that progesterone accelerates the rate of steroid dissociation from the agonist site of the glucocorticoid receptor. It has been proposed that this enhancement reflects the binding of progestins to a second steroid-binding site. Since progestins are frequently antagonists of glucocorticoid hormone action, we decided to characterize this site more fully. In particular, in this study, we investigated whether the cytosolic preparations of four separate glucocorticoid target tissues from the same species all contained this second site and whether it was similar in each case. Cytosolic extracts of rat heart, liver, kidney, and pancreas were examined. In each case it was found that the rate at which prebound tritiated dexamethasone dissociated from the glucocorticoid receptor was faster in the presence of nonradioactive progesterone. The magnitude of this effect was essentially the same in each case. These results indicated that the second site was present in each preparation. To determine if the site was similar in each extract, we studied the steroid specificity of the enhancement of dissociation. This was determined by quantitating the degree to which each of a series of test steroids could cause augmentation of dissociation. Progesterone, R-5020, medroxyprogesterone, deoxycorticosterone, 17-OH-progesterone, and cortexolone were evaluated. The results for all four cytosolic preparations showed that either progesterone or R-5020 was the most potent steroid while both cortexolone and 17-OH-progesterone were essentially without effect. Medroxyprogesterone and deoxycorticosterone were usually of intermediate potency. These results suggest that the cytosolic extracts of all glucocorticoid target tissues have a similar second steroid-binding site which demonstrates a preference for progestins and that interaction with this site causes the glucocorticoid receptor to decrease the affinity with which it binds agonists."

"...Progesterone and deoxycorticosterone could also displace the ligand but were distinctly less effective. All five of these curves are essentially parallel and reach the same end point, indicating that all are competing for the same site. In other similar studies, neither testosterone nor estradiol were found to be effective at displacing the probe."

"...The six steroids used were progesterone, cortexolone, 17-OH-progesterone, R-5020, medroxyprogesterone, and deoxycorticosterone. The first three were chosen because they have been shown to act as antiglucocorticoids in vivo (15). R-5020 and medroxyprogesterone were selected because of their similarities to progesterone."

"...The four orders of steroid potency are strikingly similar. In each case either progesterone or R-5020 is the most active steroid and these two always cause a statistically significant enhancement of dissociation. On the other hand, the other two known antiglucocorticoids, cortexolone and 17-OH progesterone, were essentially inactive in this regard in all four tissues (neither was more effective than control). Medroxyprogesterone and deoxycorticosterone were irregularly and then only weakly potent."

Steroid binding specificity of the hamster uterine progesterone receptor. - PubMed - NCBI
Relationship Between Progesterone Receptor Binding and Progestin Biological Activity

11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. - PubMed - NCBI
steroids_11b-HSD1_inhbition.png
 
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Agent207

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Why would anyone want to block anti-inflammatory cortisol hormone? What we should aim in any case is addressing the cause, mitigating the stress source that leads to inflammation.

I.e. if the cause is hypoglycemia > then eat carbs. Blocking cortisol cold turkey is like stopping the firefighters from doing their work.
 

Tarmander

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In Danny' recent interview with Ray, he asked Ray what supplements or hormones he would want on a desert island if he could only choose one or two. Ray said Progesterone would be one because if you ever get into a critical situation of high stress...like a large wound or puncture, you should take a spoonful of progesterone for its anti stress effect.
 

Evgenius

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I wonder what are the indications that can help you choose between progesterone and pregnenolone ?
 
L

lollipop

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In Danny' recent interview with Ray, he asked Ray what supplements or hormones he would want on a desert island if he could only choose one or two. Ray said Progesterone would be one because if you ever get into a critical situation of high stress...like a large wound or puncture, you should take a spoonful of progesterone for its anti stress effect.
I have directly experienced this. It works.
 
L

lollipop

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I wonder what are the indications that can help you choose between progesterone and pregnenolone ?
Ray has stated Pregnenolone for males might be better. Some men on the forum have had good results from small amounts of progesterone and lots have good results with Pregnenolone. Otherwise, experimentation seems the best.
 

DaveFoster

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In Danny' recent interview with Ray, he asked Ray what supplements or hormones he would want on a desert island if he could only choose one or two. Ray said Progesterone would be one because if you ever get into a critical situation of high stress...like a large wound or puncture, you should take a spoonful of progesterone for its anti stress effect.
That's interesting! Progesterone is the most effective supplement for me, along with caffeine (similar to progesterone,) but honestly they're all good. Emodin/beta-lapachone, aspirin, caffeine, niacinamide, and progesterone are fantastic.
 

DaveFoster

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Why would anyone want to block anti-inflammatory cortisol hormone? What we should aim in any case is addressing the cause, mitigating the stress source that leads to inflammation.

I.e. if the cause is hypoglycemia > then eat carbs. Blocking cortisol cold turkey is like stopping the firefighters from doing their work.
Cortisol suppresses the appetite (with close interaction with serotonin), so if you take out cortisol, yes there is a latent period where hypoglycemia sets in, but if you eat adequate carbohydrates you can lower your level of inflammation sooner without waiting for levels to go down on their own.

In a healthy person, hormones have elasticity (or sensitivity) to an environmental stimulus (insulin sensitivity for example.) In a chronically diseased, or aged state, there lacks a termination of the sympathetic nervous system, and the stress continues until you rely on runaway glycolysis, produce excess lactate, and cancer cells have the ability to use this lactate for energy just like normal cells. Normally, you'd get a controlled inflammatory response, but that isn't always the case with hormonal derangement brought on by whatever cause.
 

Tarmander

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That's interesting! Progesterone is the most effective supplement for me, along with caffeine (similar to progesterone,) but honestly they're all good. Emodin/beta-lapachone, aspirin, caffeine, niacinamide, and progesterone are fantastic.

Does it have feminizing effects on you?
 

DaveFoster

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Does it have feminizing effects on you?
Yeah, but it tones my aggression so I can communicate and do my work. I also take K2, DHEA and preg, so that might offset it.
 

lampofred

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Is there a way to increase the progresterone/estrogen ratio without taking hormones or supplements?
 

DaveFoster

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Is there a way to increase the progresterone/estrogen ratio without taking hormones or supplements?
Mitigate the effects of intestinal flora: carrot salad, activated charcoal, and cascara sagrada for a quick transit all taken away from meals. Coffee as well.
 
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haidut

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Why would anyone want to block anti-inflammatory cortisol hormone? What we should aim in any case is addressing the cause, mitigating the stress source that leads to inflammation.

I.e. if the cause is hypoglycemia > then eat carbs. Blocking cortisol cold turkey is like stopping the firefighters from doing their work.

When you are a young child you produce very little cortisol and still have low inflammation. The beginning of puberty truly marks the beginning of the aging process as the adrenals start to take over the steroidal metabolism and gonadal function gradually declines. So, if enough pregnenolone and progesterone are present then you need very little (if any) cortisol. Cortisol is a really bad steroid, and it increases chronically with aging most likely as a result of the PUFA overload which also grows with age. Cortisol is also likely the main driver of the gross features of aging.
“The main features of aging can be produced... | Ray Peat Forum
The goal is to provide steroids that can replace its function without the side effects. Pregnenolone and progesterone are two such steroids. Testosterone, DHT and maybe even androsterone have their role as well in opposing cortisol, but pregnenolone and progesterone are the preferred signals of youth that tell cortisol to stay low.
 

haidut

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I wonder what are the indications that can help you choose between progesterone and pregnenolone ?

I think both can be used for some time, even by males. A dose of 30mg pregnenolone and 10mg progesterone can go a long way and the pregnenolone prevents the progesterone from being too anti-androgenic. Interestingly, this only seems to happen when used together. When used on their own, both can be anti-androgenic in some males. When used together, the build up of progsterone and its known stimulation of the 17,20-lyase enzyme makes pregnenenolone go down the DHEA pathway...Not sure, just a guess based on observations and some biochemistry.
 

Regina

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Cortisol suppresses the appetite (with close interaction with serotonin), so if you take out cortisol, yes there is a latent period where hypoglycemia sets in, but if you eat adequate carbohydrates you can lower your level of inflammation sooner without waiting for levels to go down on their own.

In a healthy person, hormones have elasticity (or sensitivity) to an environmental stimulus (insulin sensitivity for example.) In a chronically diseased, or aged state, there lacks a termination of the sympathetic nervous system, and the stress continues until you rely on runaway glycolysis, produce excess lactate, and cancer cells have the ability to use this lactate for energy just like normal cells. Normally, you'd get a controlled inflammatory response, but that isn't always the case with hormonal derangement brought on by whatever cause.
Great explanation Dave! Thx.
 

poilochio

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Mitigate the effects of intestinal flora: carrot salad, activated charcoal, and cascara sagrada for a quick transit all taken away from meals. Coffee as well.
hey Dave what kind of dose of Activated Charcoal would be a good starting dose?
for lets say bloating in a female?
 
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I think both can be used for some time, even by males. A dose of 30mg pregnenolone and 10mg progesterone can go a long way and the pregnenolone prevents the progesterone from being too anti-androgenic. Interestingly, this only seems to happen when used together. When used on their own, both can be anti-androgenic in some males. When used together, the build up of progsterone and its known stimulation of the 17,20-lyase enzyme makes pregnenenolone go down the DHEA pathway...Not sure, just a guess based on observations and some biochemistry.

ive experienced this as well... it seems like preg moreso goes down the DHEA line, and might leave some progesterone out of the loop? or do you know what is happening? i always thought from taking finasteride that the progesterone side was just messed up and all the hormones went down the DHEA side
 

haidut

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ive experienced this as well... it seems like preg moreso goes down the DHEA line, and might leave some progesterone out of the loop? or do you know what is happening? i always thought from taking finasteride that the progesterone side was just messed up and all the hormones went down the DHEA side

I think it is very difficult to skew the cascade in favor of DHEA unless the person has PCOS or something similar. The 17,20-lyase is very tightly regulated and in most people it is probably downregulated as a result of low thyroid function. It is much more likely that taking higher dose pregnenolone raises pregnenolone sulfate and 17-OH-pregnenolone until it slowly gets metabolized into other steroids. High levels of 17OHP also decrease 17,20-lyase activity.
17α-Hydroxypregnenolone - Wikipedia
 
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