How to down regulate androgen receptors? (PFS)

[Mister]

Does anyone know effective options to down regulate androgen receptors?

The androgen receptor deregulation seems to be the most accepted PFS theory.

Of particular interest, androgen receptor expression (AR) was found to be significantly higher in patients compared to controls, in the absence of differences in serum markers indicating AR activity or trinucleotide repeat variation. The authors suggested that AR overexpression in response to an androgen-deficient state may negatively affect multiple tissues throughout the body, could be responsible for the sexual symptoms of Post-Finasteride Syndrome, and - if overexpressed in other tissues - may be involved in other symptomatic domains, including cognitive symptoms.

Differential Gene Expression in Post-Finasteride Syndrome Patients — PFSNetwork.org

Evidence of gene expression correlating with observed biologic differences, including significant Androgen Receptor overexpression, was reported in a landmark investigation of patients with post-finasteride syndrome.

www.pfsnetwork.org

@Hans You know how to do this?

 

[aliml]

Niclosamide (salicylic acid derivative) inhibits androgen receptor variants expression.

Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing…

www.sciencedirect.com

 

[Snarf]

Down regulating androgen receptors doesnt seem sensible to me.

Wouldnt up regulated AR make it easier to gain muscle? I havent heard of pfs sufferers being able to build muscle easily.

 

[Mister]

Down regulating androgen receptors doesnt seem sensible to me.

Wouldnt up regulated AR make it easier to gain muscle? I havent heard of pfs sufferers being able to build muscle easily.

This is not about gaining muscle but about trying to recover PFS (post finasteride syndrome). Read the op.

 

[Snarf]

This is not about gaining muscle but about trying to recover PFS (post finasteride syndrome). Read the op.

I know its not about gaining muscle. Im just saying that if up regulated androgen receptors were the problem for pfs sufferers, then wouldnt a side effect of that be that they could build muscle easily?
Down regulating androgen receptors would be the last thing I would, I can imagine that would make things even worse.

 

[Mister]

I know its not about gaining muscle. Im just saying that if up regulated androgen receptors were the problem for pfs sufferers, then wouldnt a side effect of that be that they could build muscle easily?
Down regulating androgen receptors would be the last thing I would, I can imagine that would make things even worse.

Oh I see. Yeah I don't hink most guys with PFS have a problem building muscle.

But research showed up regulated androgen receptors hence trying to downregulate them again.

Here's one guy who claims he got cured with proviron, and he says high dose proviron down regulates receptors:

Cured after 11 years

Welcome to our community. Please fill in the following template as a way of introducing yourself, and helping others to understand your background and situation. Where are you from (country)? Sweden How did you find this forum (Google search – if so, what search terms? Via link from a forum or...

forum.propeciahelp.com

"Took finasteride for 5 months. I felt fine while taking it but it gave me gyno so I stopped. After stopping, I got ED, extreme fatigue, brain fog, no libido and lethargy. I tried just about everything over 11 years. I also tried testosterone treatment but it had almost no effect regardless of dosage.


I read a case study by Neurologist David Clark (link 108) where someone had similar symptoms but there was no mention of finasteride or PFS. His issue wasn’t the hormones being too low but rather too high which caused receptor issues so they decided to down regulate them.


My take on PFS is that the receptors become hyper sensitive due to getting so little DHT for a long period of time. So when things compensate or go back to normal, they are too sensitive and you end up in a miserable state.


I decided to test that by supplementing DHT (proviron) and despite it being a general feel-good hormone for most, I felt absolutely dreadful when taking it. My symptoms increased by 10x and I couldn’t function but it made me realize I was on to something. I felt like my options were either to permanently decrease DHT in some way or decrease the sensitivity of the receptors.


The receptors likely became hyper sensitive by getting so little DHT for a prolonged period of time while taking finasteride. So I tried the opposite to reverse the situation. I took a large amount of DHT (proviron) for 7 weeks at 200 mg per day to reduce receptor sensitivity to DHT.


At first, I felt absolutely miserable when doing so, it is the worst I’ve felt in my life and I was unable to do almost anything but after some weeks it became more tolerable as the receptors lost some of their sensitivity.


After stopping 7 weeks later (when I ran out of my proviron), things felt off for a few weeks but then after around two months I got back to my pre-PFS state. Now and for the past six months, I feel great, my libido is great, mental issues are gone, ED is gone. This after having PFS constantly for 11 years. My life is finally back."

 

[aliml]

Niclosamide (salicylic acid derivative) inhibits androgen receptor variants expression.

Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing…

www.sciencedirect.com

Substances That May Decrease Androgen Receptor:

-- DHT
-- Niclosamide
-- Genistein
-- Resveratrol
-- Sodium Selenite
-- Curcumin
-- Capsaicin
-- Sulforaphane
-- Ketoconazole
-- Selenium
-- Zinc
-- Garlic Extract
-- Vitamin D
-- Selenomethionine
-- Vitamin E (Tocopherols)
-- Grape Seed Extract
-- Melatonin
-- NAC
-- Silymarin
-- GLA
-- Lycopene
-- Green Coffee Bean Extract
-- Nitazoxanide
-- Eugenol
-- Tetracycline
-- Propolis
-- Butyric Acid
-- EGCG
-- Methylfolate
-- Coumestrol
-- Paroxetine
-- Duloxetine
-- Letrozole
-- Megestrol
-- Budesonide
-- Clomiphene

Selfdecode

Use SelfDecode to get personalized health recommendations based on your genes. Get started today with an existing DNA file or order a SelfDecode DNA kit!

selfdecode.com

 

[Highserotonin90]

What increases?

 

[DonLore]

Doesnt make any sense that high androgen receptor sensitivity would be a bad thing. How would that cause problems, you should feel androgenic with high AR density

 

[MyUsernameHere]

My guess... Androgen receptors are upregulated because local 5-AR production is very low and tissues are starved for DHT. Serum DHT tests don't pick this up since DHT is an autocrine hormone.

 

[cupofcoffee]

Doesnt make any sense that high androgen receptor sensitivity would be a bad thing. How would that cause problems, you should feel androgenic with high AR density

The relationship doesn't have to be necessarly linear, AR being too overexpressed could easily lead toxic levels of AR signaling and loss of function

I haven't read it fully but this article from propecia help looks very interesting

Propeciahelp.com - Discussion forum for Post-Finasteride Syndrome

(i don't have pfs but i'm interested in the topic)

 

[Mister]

The relationship doesn't have to be necessarly linear, AR being too overexpressed could easily lead toxic levels of AR signaling and lost of function

I haven't read it fully but this article from propecia help looks very interesting

Propeciahelp.com - Discussion forum for Post-Finasteride Syndrome

(i don't have pfs but i'm interested in the topic)

That's a very interesting article indeed.

"Presuming a 60% reduction of basal DHT levels during finasteride use, cells epigenetically adapted to a depletion of androgenic signaling owing to the pharmacological reduction of DHT would be exposed to a 300% increase in DHT upon cessation. As molecular level investigation has revealed a persistent elevation in expression of the androgen receptor in symptomatic tissue of a PFS cohort, this may entail a deleterious ligand-dependent effect in alignment with the demonstrated in vitro and in vivo models discussed. Application of such a conceptual framework to the pathology of PFS is not unprecedented. Professor Charles Ryan explained the tissue response to testosterone in terms of a “bell curve” in his book The Virility Paradox. He wrote of PFS: “I think this is what we are seeing here. With a greater concentration of receptors, the organ becomes more sensitive to testosterone and at a certain point, paradoxically, that sensitivity may shut down” (Ryan, 2018)."

@aliml Interesting study and thanks for that list, will look into it some more.

 

[aliml]

What increases?

DHEA
Ashwagandha
Ginger
Mucuna Pruriens
Shilajit
Tongkat Ali
Black Cumin Seed
[...]
Octacosanol
Beta-Carotene
Beta-Sitosterol
Boron
Gamma-Sitosterol
Testosterone
[...]

 

[Mister]

@aliml what do you think about this user's comment?

Europe PMC

Europe PMC is an archive of life sciences journal literature.

europepmc.org

Androgens seem to upregulate AR, not downregulate it.

Then again, so does removing androgens.

Early upregulation of AR and steroidogenesis enzyme expression after 3 months of androgen-deprivation therapy - BMC Urology

Background Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PCa). However, PCa recurrence and progression rates during ADT are high. Until now, there has been no evidence regarding when progression begins. This study evaluated the gene expression of...

bmcurol.biomedcentral.com

The situation is not clear cut at all.

 

[Mister]

Some interesting comments from Haidut in this old thread:

Proviron Is Curing My PFS Symptoms But Need Some Help

He is partially right. While it's true that DHT itself is estrogen antagonist, it won't powerfully kill estrogen like an AI. But it's still a decent estrogen antagonist. But I don't think that "estradiol can continue to build up" (WTF?) If you don't have a really high estrogen/prolactin...

raypeatforum.com

Btw, @Sexypizza (OP from that thread) how are you doing now? You recovered from PFS?

 

[Mister]

Vit D is also interesting:

Vitamin D and androgen receptors​

Not only does vitamin D increase testosterone, but it also has to potential to bind to the androgen receptor itself.


“An extra mechanism of VD on erectile function seems to function via binding to T receptors. Computer (in silico) modeling shows that besides activating the VDR, 1,25-D displays high affinity for some of the body’s other nuclear receptors. This suggests that when 1,25-D increases above its normal range, it binds the α/β thyroid, the glucocorticoid, and the T receptors, displacing their native ligands [53]. Marshall [54] showed the symmetry with which endogenous ligands exhibited very similar affinities across some members of the type 1 nuclear receptor family [54]. For example, 1,25-D docked into the VDR with a (nanomolar) Kd of 8.48, but also exhibited a Kd of 8.05 into the T receptor.” (R)


Lastly, vitamin D increases the duration that the androgens bind to the androgen receptors, by inhibiting glucuronidase. Longer binding = stronger effect.

Get your penis to work with this big, bad steroid » TESTONATION

If I had to pick one thing to optimize for erectile function before anything else… It would be vitamin D. Although the name implies that it’s a vitamin, it’s actually a steroid. It’s so strong, it potentiates the effects of steroids, such as progesterone, testosterone and DHT. Not only that, but...

men-elite.com

 

[Mister]

Here's an article how to RAISE receptors:

ANDROGEN RECEPTORS: 27 best ways to increase it » TESTONATION

Low androgen receptor expression could be the reason for your symptoms of low androgens. What would it help to have high androgens, but they can’t do anything? Do you know that feeling when you have tried so many different things to increase testosterone for your mood, libido, muscle tone...

men-elite.com

 

[Mister]

Found this interesting:

Carnitine Stimulates The Synthesis Of Androgen Receptors​

Prior to the discovery of carnitine 2 stimulating the production of more androgen receptors, this was a fantasy only imagined in the minds of researchers and athletes alike. Yes, carnitine 2 if one of the very few things that can bring about an increase in the number of androgen receptors found in the male body, as well as “upregulating” them, or making more sensitive to the effects of androgens[

But why is this important? Because it is considered the rate limiting step on how fast you can build muscle. A good analogy to put this into perspective would be to consider testosterone as “passengers” at a bus terminal, and the buses as “androgen receptors”.

There is a limited number of buses/seats, which means that only so many people can be accommodated at once. Increase the number of buses (receptors), and in turn more passengers can board and get to where they need to be (the testosterone).

Thus, [carnitine] is one of the few things that can yield greater results than that obtained from increasing testosterone levels only. As a result, greater muscle synthesis occurred, and better preservation of lean muscle tissue
while dieting or trying to reduce body fat.




Screen Shot 2020-08-20 at 11.16.34 AM787×523 31.2 KB

---

On this same topic, weight training, tribulus, and intermittent fasting both have shown to increase AR density just like carnitine.

 

[ChemHead]

Down regulating androgen receptors doesnt seem sensible to me.

Wouldnt up regulated AR make it easier to gain muscle? I havent heard of pfs sufferers being able to build muscle easily.

No. The problem is in the brain. If you overexpressed AR in only muscle tissue, then maybe this would be the case. The problem is that if AR is overexpressed in the pituitary, you're automatically going to be hypogonadal because you're receiving a lot of negative feedback for little steroidogenesis.

The best route would be to expose your body to physiological concentration of DHT for an extended period of time... Maybe 4-6 weeks.. And then stop and allow a few weeks for hpta to readjust. After these few weeks, when your gonadotropin synthesis is restarted, hopefully your AR expression will be lower. You need to get your body to express higher levels of 5AR so that there's a better balance of androgen metabolism between 5a-reduced steroids and estrogens. When you're in a chronic state of low androgenic activity and elevated estrogenic activity, AR expression will be upregulated and this will cause lowered steroidogenesis due to hypersensitivity in the pituitary.

The other possible route, may be to use an androgen receptor antagonist for a couple weeks. An androgen receptor antagonist will cause upregulation of steroidogenesis. The hope also is that it will cause an upregulation of 5AR expression, but I've not been able to find any scientific research to support that this would happen... Only the inverse... That a 5AR antagonist will cause AR overexpression.

 

[ChemHead]

The receptors likely became hyper sensitive by getting so little DHT for a prolonged period of time while taking finasteride. So I tried the opposite to reverse the situation. I took a large amount of DHT (proviron) for 7 weeks at 200 mg per day to reduce receptor sensitivity to DHT.


At first, I felt absolutely miserable when doing so, it is the worst I’ve felt in my life and I was unable to do almost anything but after some weeks it became more tolerable as the receptors lost some of their sensitivity.

The reason he felt miserable while taking the DHT wasn't really from the DHT itself. It was due to the shutdown of of gonadotropin synthesis. So, while he had reasonable or even high levels of DHT, his testicular steroidogenesis was reduced and he was deficient in every other steroid made starting from pregnenolone down each unique steroidogenic pathway.

After stopping 7 weeks later (when I ran out of my proviron), things felt off for a few weeks but then after around two months I got back to my pre-PFS state. Now and for the past six months, I feel great, my libido is great, mental issues are gone, ED is gone. This after having PFS constantly for 11 years. My life is finally back."

This period of time where "things felt off" was due to having simultaneously low steroidogenesis and, now, no DHT since he ceased using that. During that period is where the HPTA readjusts and begins producing gonadotropins. As steroidogenesis returns, the hope is that AR expression is lowered and 5AR expression is restored and it seems like that's what happened for him.