Upregulated GR( cortisol) receptor theory

[Helen]

Thought I start this thread, since a lot of people are experimenting with this on PSSD forum, and we have more and more studies for both PSSD and PFS about this.

Here I found an interesting one. Does increased expression of glucocorticoid receptor support application of antagonists to this receptor for the treatment of castration resistant prostate cancer? - Hirayama - AME Medical Journal

 

[talkingant]

First, glucocorticoids suppress adrenal androgen synthesis through a negative feedback on the pituitary gland

This could mean, people with overexpressed GR are having their adrenal androgens suppressed as it is over sensitive to cortisol.

"recent speculation that increased expression of GR following exposure to AR blockade may be a resistance mechanism driving CRPC"

This suggests that reducing AR activation, like what happens when you reduce DHT with fin, could increase GR expression.


I'm reminded of the guy on PropeciaHelp who claimed he was cured after a large dose infusion of methylprednisolone. Also the PSSD guy who claimed he was cured after 3 months of licorice root (which blocks breakdown of cortisol thus raising levels/GR activation).

People have experimented with licorice root and usually report bad side effects like increased anxiety while on it. Most people didn't take it for very long.

A big question here is what is the optimal protocol to downregulate GR? Can you use a mix of corticosteroids and licorice root? Do you have to elevate GR activation for multiple months? If people got PSSD/PFS within 24hrs after a single pill, and GR got overexpressed that fast, it seems like there should be a way to just as quickly downregulate it. Also, got to make sure the changes stick.

Mesolimbo on PSSDForum is currently experimenting with licorice roots and corticosteroids AFAIK. It will be interesting to see what he reports in the coming weeks.

 

[Nighteyes]

Should not quercetin be helpful for This as well? I believe we have discussed previously on here that it downregulates GR

 

[Helen]

@joekool Joe, may be anavar breaks down cortisol receptor overall, which it says that anavar does not block it , does not inhibit the connection part, but actually does something to the transcriptional part of cortisol receptor. Thus people have very high cortisol for a long time after coming off anvar. some for a year.

May be overtime, it kills it and cortisol goes higher. and boom problem solved for slow oxidizer.

So it seems we have 2 cases, increased AR case and increased GR case.


In the increased GR case, it increases SHBG and also blocks the receptor androgen receptor by lowering demethylating enzyme. by killing estrogen since demethylating of histone is done with amine oxidase - copper enzyme. . So histone stays methylated and this lowers the action of AR.

usually in this case. acetylation goes way up. thus some people felt better on lysine. But if GR is strong, body is losing zinc from zinc finger, to make it weaker

and now you got double whammy on androgen receptor. first it stays methylated since cortisol lowers estradiol by increasing SBHG

and then body is losing zinc also since GR receptor is too strong.

So androgen receptor which usually has 3 ways to upregulate, in any cases of emergencies, now has only 1 left , which is increasing androgen receptor density , which it does.


I guess with upregulation of AR , same thing happens and now cortisol receptor is in trouble.


Anavar blocks both AR and GR.

Same as RU. RU is antiandrogen. anti progestin and anti cortisol

 

[Helen]

This could mean, people with overexpressed GR are having their adrenal androgens suppressed as it is over sensitive to cortisol.



This suggests that reducing AR activation, like what happens when you reduce DHT with fin, could increase GR expression.


I'm reminded of the guy on PropeciaHelp who claimed he was cured after a large dose infusion of methylprednisolone. Also the PSSD guy who claimed he was cured after 3 months of licorice root (which blocks breakdown of cortisol thus raising levels/GR activation).

People have experimented with licorice root and usually report bad side effects like increased anxiety while on it. Most people didn't take it for very long.

A big question here is what is the optimal protocol to downregulate GR? Can you use a mix of corticosteroids and licorice root? Do you have to elevate GR activation for multiple months? If people got PSSD/PFS within 24hrs after a single pill, and GR got overexpressed that fast, it seems like there should be a way to just as quickly downregulate it. Also, got to make sure the changes stick.

Mesolimbo on PSSDForum is currently experimenting with licorice roots and corticosteroids AFAIK. It will be interesting to see what he reports in the coming weeks.

Cytochrome from propecia were on glucorticoids for 6 months and came off, then waited for 2 months and recovered.

Wuf took high dosages just recently and feeling so much better. But it took a while after he came off to stabilize also, about a month

 

[Helen]

@talkingant @joekool but I want to point out. that we have different cases of PFS and PSSD.

Look at raincoast = high copper, wuf = high copper, aflac guy extremely high copper


Some folks have Gilberts, and may be can't clear estrogen.


@talkingant and @barbaar you guys are PSSD, you have high histidine. means it is not converted to histamine, thus no libido.


But some folks with high copper are different. Copper is breaking their histamine and histidine actually gets converted too much into histamine, and when they bind copper with resveratrol lets say, boom insane libido like in Aflacs case.

 

[TubZy]

Anavar is not anti prog though. For me RU and anavar did not feel the same. Anavar still had POIS symptoms and other lingering symptoms. Plus it needs to get across the BBB to really work which RU does in higher doses. I'm pretty sure anavar blocks cortisol much more in the muscle not sure how much makes it across the BBB..it may require way higher doses that liver can't handle in order to make it across.

 

[tanedout]

@Helen so potentially curcumin could be useful for those with high cortisol, due to the following?

(Curcumin) also lowered blood cortisol levels and increased cortisol sensitivity (increased Glucocorticoid Receptor Expression)

Top 37 Curcumin / Turmeric Benefits + Side Effects, Dosage - SelfHacked

 

[gaivs]

Cytochrome from propecia were on glucorticoids for 6 months and came off, then waited for 2 months and recovered.

Wuf took high dosages just recently and feeling so much better. But it took a while after he came off to stabilize also, about a month

Some time ago I had to take a low dose (antiinflamatory dose) of prednisone for 3 days and I felt good also.

Cytochrome said his protocol was 0.5 mg of dexamethasone at night 7 days on and 7 days off. Do you think this is the best protocol? Do you have a better idea?

 

[Helen]

1) I think may be in some people GR is overexpressed, this raises SHBG, but since SHBG has much much higher affinity to DHT than to estradiol. This creates estrogen like state. plus body tries to fight overexpressed GR and raises CBG which binds progesterone. and may be pregnenolone.


this is why in CSF fluids we see, low DHT, low preg, low progesterone. and low estrogen.




2) and in second case with suppressed androgens, may be estrogen is overexpressed. this raises CBG( transcortin) which binds cortisol, aldosterone, and progesterone.

And since it binds progesterone, this also creates estrogen state. and very low available cortisol. but in blood both progesterone and cortisol are high .


and thus we also get to have low DHT, low estro , low progesterone and pregnenolone in CSF.



@talkingant @joekool @Boris @tanedout

 

[Helen]

Of course it could be that AR is overexpressed in the second case. instead. this causes low estrogen , low CBG and high cortisol state.

We should test CBG in fast and slow oxidizers, it could give us more clue

 

[Helen]

@talkingant Escitalopram alters gene expression and HPA axis reactivity in rats following chronic overexpression of corticotropin-releasing factor from the central amygdala


So it says in here that SSRI downregulate CRF receptor density, thus ACTH falls and GR gets overexpressed.

Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin.

This says that it stops testosterone production.


So now if you look at Melcangi study, testosterone is not being converted into DHT in the brain.

And testosterone is high. body tries to bind testosterone with SHBG so it does not enter the CSF.

Since testosterone is high. DHEA is not being converted into testosterone and also high.

DHEA is not bound with CBG or SHBG , this is why it is high in CSF.

But DHEA is controlled by ACTH. So high DHEA will suppress ACTH.


And since we know that CRF receptor could be downregulated, this does not allow CRF to upregulate back. And serotonin as CRF releaser also stays inhibited.

Thus we see high tryptophan in your blood. This high free tryptophan increases acetycholinesterase which breaks down acetycholine. Thus no penis sensitivity , erection problems, all the acetylcholine problems , no sweating.



this could explain why people feel better on CORTISOL supplement plus serotonin agonist. At the same time.



And also explains why they can feel like shit on cyproheptadine and cured on withdrawal. Since cyproheptadine upregulates CRF receptor and serotonin receptor at the same time.

 

[Helen]

@talkingant Isn't the cure tribulus plus cyprohepdatine cycling? Downregulate AR. This lowers test plus DHEA plus downregulates GR.

Now block serotonin receptor and CRF, upregulating them. So you go back exactly to where you came from?


IT is exactly the opposite of what you were doing with SSRI.




I bet people who tried cyprohepdatine felt like shit on it. and then cured in 3-4 days and then back to shit, since androgen receptor does not allow this to come back.

But if you run it along tribulus or anything that increases 5AR. then this will downregulate GR also.


still thinking about it

 

[manu]

@Helen
I don't have or know anything about PSSD but I can't ignore my sometimes-incredible memory:

CYPRO is a game changer for my somehow acquired PSSD from Ashwagandha usage.

What seems to happen is that Cypro at doses of 1mg seems to make my symptoms worse, but then 2-3 days later, it makes me feel cured of all my PSSD symptoms. I also found combining it with strong liver herbs like artichoke extract etc, to really help.
In addition, I STRONGLY believe that the use of ALCAR the day after makes me feel INCREDIBLE. ALCAR feels very very different under Cypro.
5-HT1A agonism?

Cyproheptadine - A Wonder Drug?

 

[talkingant]

A few people did try cypro on PSSDForum and felt better for a few days after taking it. It seems like a low dose (~1mg) is best, and to also support acetylcholine and dopamine while on it. 5HT1A receptors could also be involved as it appears they regulate cortisol as well.

Cypro might also upregulate histamine receptors, which we have hypothesized to be involved in libido and nicely summarized recently by Mesolimbo.

It's an interesting pathway, need to do some more thinking about this.

 

[Helen]

@talkingant Histidine is not being converted into histamine , thus you have high histidine, in blood, same as barbaar.

Cortisol controls that enzyme. cortisol stops the conversion.

 

[freeflow]

@talkingant Isn't the cure tribulus plus cyprohepdatine cycling? Downregulate AR. This lowers test plus DHEA plus downregulates GR.

Now block serotonin receptor and CRF, upregulating them. So you go back exactly to where you came from?


IT is exactly the opposite of what you were doing with SSRI.




I bet people who tried cyprohepdatine felt like shit on it. and then cured in 3-4 days and then back to shit, since androgen receptor does not allow this to come back.

But if you run it along tribulus or anything that increases 5AR. then this will downregulate GR also.


still thinking about it

There is a guy on ray peat forum who feels shit on cypro, then later feels insanely good which goes away. Of course they have no idea whats happening

I see @talkingant just copied the guy.

 

[brix]

Cypro kills me when I take it alone. Immediate depression, fatigue, low libido for 2 days. I hypothesize I have high serotonin too but it doesn’t help unless I take thyroid or some type of dopamine agonist with it.

 

[Helen]

Cypro kills me when I take it alone. Immediate depression, fatigue, low libido for 2 days. I hypothesize I have high serotonin too but it doesn’t help unless I take thyroid or some type of dopamine agonist with it.

Hey are you sweating like crazy?

if yes, you could be high acetylcholine person, since progesterone and progestines are known to upregulate acetylcholine receptor. Since progesterone is acetylcholine receptor antagonist.

then acetylcholine raises cortisol and keep it high and on hairtest you can look like fast oxidizer.

 

[brix]

Hey are you sweating like crazy?

if yes, you could be high acetylcholine person, since progesterone and progestines are known to upregulate acetylcholine receptor. Since progesterone is acetylcholine receptor antagonist.

then acetylcholine raises cortisol and keep it high and on hairtest you can look like fast oxidizer.

I sweat like a pig in heat. I figured I have very high progesterone but haven’t had it tested. Probably why Ella worked so well for me.

I’m confused; you say prog upregulates acetylcholine receptor but also is antagonist. Wouldn’t something that acts as an antagonist downregulate a receptor?

@Helen thoughts?