Resistance to Androgen Deprivation

General Discussion
#1

So Fin, SSRIs and Accutane could all be considered to have anti-androgen properties.
How is that combated?
AR overexpression or amplification.
Another standout Glucocorticoid Receptor Upregulation.

How this has been looked at here, is the thought of continued AR overexpression all based on that 8 person symptomatic PFS study?
Everything else seems to more so support the thought that chronic downregulation/decreased or weak expression of the AR gene makes more sense in PFS.
Am I wrong?

Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer

https://journals.sagepub.com/doi/10.4137/CMO.Ss34534?icid=int.sj-full-text.similar-articles.2&

^This is what you want right? Resistance to Androgen Deprivation?

These studies are in conflict.
https://onlinelibrary.wiley.com/doi/full/10.1111/andr.12297

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#2

As much as I understood about most recent theories of science on PFS, AR gets overexpressed during 5ari, and after cessation when a huge wave of androgens return they shut down in response = AR become downregulated, thats why we dont profit anything of our androgens in our system, neither on skin, neither on penis, nor on muscles or brains.

#3

This is the line right here, its on the home page. Its part of the main ongoing theory.
This is increased AR expression or upregulation.

Post-Finasteride Syndrome as an Epigenetic Post-Androgen Deprivation Syndrome: A potential pathological link between Drug-Induced Androgen Receptor Overexpression and Polyglutamine Toxicity

“Persistent AR overexpression has been established in symptomatic tissue of PFS patients and is a mechanistic consequence of androgen deprivation.”

^Androgens can regulate their own expression, there are other studies that are in direct conflict with this.

Example, a consequence of androgen deprivation (meaning low serum levels or tissue) can also lead to decreased AR expression.

Androgens such as testosterone or dht can upregulate ARs.

The dutasteride study states the opposite,
Androgen serum levels return, AR expression stays decreased, become insensitive to circulating androgens.

^and that is PFS.

It would obviously be a pretty big deal to get this part right, because otherwise you are getting into the strange realm of wanting to go back on Fin or take anti-androgens. Does that make sense?

Maybe im looking at this wrong, anyone feel free to chime in.

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#4

@guitarman01, I agree - the conflicting studies and hypotheses really muddy the waters of our collective understanding.

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#5

You see, thats so confusing to me: if receptors are overexpressed, I would naively assume that I get hyperandrogenic with bigger muscles, higher libido, stronger body hair growth, faster pattern balding, more aggression and mood etc.

Yet we experience the opposite. While we have an AR overexpression. This paradox I could not understand yet. Thanks if you help with that

#6

There is evidence that overstimulation of receptors actually causes them to shut down and affects their ability to signal.

#7

See my first text in this topic above:

So I understand it right?

#8

Except the AR stays upregulated, almost locked into that state and due to the upregulation and the saturation effect, they shut down.

#9

Which means none of our tissues can get androgen signals or their effect by in this condition?
Thanks man, I guess I understand it now…

#10

That’s the theory. It’s just a theory, but there seems to be evidence of AR upregulation in penile tissue at least in PFS sufferers.

#11

It wakes some hope that science has a direction to investigate at least. Otherwise we must hope our body’s capacity in self re-adjustment.

#12

Interesting article regarding this:

“Di Loreto et al. showed their experience in patients with persistent symptoms after withdrawing finasteride 1mg/day for androgenetic alopecia who had undergone a foreskin biopsy in order to determine androgen receptor density, resulting much higher in cases than in controls. This data could imply a fundamental role of 5AR in the expression of the androgen receptor18. However, evidence differs in some in vitro studies with prostate cancer cells exposed to finasteride, in which the expression of the androgen receptor is downregulated [36], although the physiopathology could differ with a different population or target.”

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#13

And that just may be our problem. In some tissues receptors are upregulated persistently while in other tissues they’re downregulated persistently. So a substance which is an AR receptor antagonist may benefit the tissues wherein the receptors are upregulated by reducing saturation but negatively affect tissues wherein the receptors are downregulated. Taking an AR receptor agonist may have the opposite effect. The same applies when it comes to taking hormones directly - if the receptors aren’t free to up/downregulate dynamically, boosting, say, T levels could cause certain tissue to be pushed into signal saturation whilst other tissue may then have an optimal ligand-receptor balance which improves functioning.

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#14

Exactly, targeted tissue specific AR therapy could be only thing rescue us

#15

A targeted androgen receptor antagonist could theoretically do the job here.
By binding to and blocking androgen receptors, the specific tissues would theoretically de-methylate and upregulate ar sensitivity. Then after slowly withdrawing the ar antagonist, we would hopefully be in a better place than we were prior to introducing the antangonist.

I’ve read that RU58841 (used by many as a topical alternative to finasteride in the hairloss community) is supposed to have more localized effects than other ar antagonists (due to its short half life).

Just wondering if applying this to our male parts over the course of a month would desensitize them. Not sure if anybody would be crazy enough to try this out. :sweat_smile:

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#16

Are there some studies on this you could link?
“There is evidence that overstimulation of receptors actually causes them to shut down and affects their ability to signal.”

The dutasteride study I posted showed that even when castrated the AR receptor was temporarily overexpressed in the prostate, but eventually dropped to below pre-castration levels.
So when you say shut down do you mean a different mechanism then decreased expression?

From that study,
“These facts could explain the fact that sexual side effects caused by 5α‐R inhibitors persist even after the cessation of medication, meaning that although serum androgen levels can be restored to its original condition after about 1 week from cessation of medication, altered expression of tissue hormonal receptors inhibit the proper reaction to androgen.”

I could almost relate this to how Accutane works.
There is sometimes an initial surge of acne or temporarily worsening when first starting Accutane treatment.
Could this be a brief period of increased AR expression as a type of resistance?

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#17

Heres maybe another head scratcher for me. Another thread thats had alot of interest.

Androgen receptor overexpression and sensitivity to hormones reversed by epigenetic therapy that restores Pur-α to a transcriptional repressor complex of AR deregulated in HRPC

^HDACI’s that restore Purα and decrease AR mRNA levels reverse the resistance to antiandrogens.

So you want to decrease your resistance to antiandrogens?
So next time you take Fin, Accutane or milk thistle you have less resistance to its antiandrogen effects?
So everyone just needs to go back on their offending drug?
This is where the thought of tapering comes from?
idk.

“If our problem is AR insensitivity to testosterone HDACI-bicalutamide could be the solution.”
^Does this first comment make sense?
It literally says in the title,
AR overexpression = Sensitivity to hormones

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#18

So again,
Decrease AR mRNA levels reverse the resistance to antiandrogens or
Decrease AR expression=decrease resistance to antiandrogens.

Looking through that thread, it seems like thats the goal?
The only “antiandrogen” that could maybe make sense to me is Retinoic acid,(not vitamin a from diet or supplements) but idk.

Are there some studies on this you could link?
“There is evidence that overstimulation of receptors actually causes them to shut down and affects their ability to signal.”

^Was hoping for an answer on this from anybody?
If this were the case you would think CRPC or HRPC wouldnt be an issue.

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#19

I guess I’ll go first.
AR overexpression as a good thing.
Counterargument?

One note, they use anti-androgens, AR antagonists and AR inhibitors interchangeably in this study.

Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

In the majority of cases, CRPC is accompanied by reactivation of the AR signaling axis so that the receptor regulates its numerous target genes including PSA. Not surprisingly, an impressive repertoire of mechanisms has been identified that reactivate the AR signaling axis. These include upregulation of CYP17 [5], amplification of the AR gene [6], expression of constitutive AR splice variants [7, 8], or mutation of the AR itself [9–12].

Androgen receptor: what we know and what we expect in …

(https://pubmed.ncbi.nlm.nih.gov/30128923/)

Aug 20, 2018 — The multiple AR -related mechanisms promoting the development of CRPC are as follows: (1) enhanced transformation and increased synthesis of intratumoral androgen; (2) AR overexpression , which enables CRPC to be hypersensitive to low levels of androgen; (3) AR cofactors, which enhanced AR transactivation; (4) AR -spliced …

Accumulating evidence finds that AR protein is elevated in approximately 80~90% CRPC patients, leading to AR signaling activation

#20

" A group of Italian researchers gave finasteride to rats and noticed that the number of androgen receptors in their brains went up. Moreover, the effects persisted long after the drug had been discontinued.…[T]hey then called in men with PFS, took skin from the penis and found that the density of androgen receptors in men with PFS was about twice that of those without. Now, remember the idea of the testosterone bell curve and damping effects (little testosterone, little growth, more testosterone, more growth, even more testosterone, reduced growth)? 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."

And it makes sense. If our receptors were functionally overexpressed, we would get huge libido and muscle mass. So we have overexpressed AR, yet they shut down, so pratically we have no AR