Why is increased Androgen Expression a bad thing or considered causative in PFS?

General Discussion
#1

I assume overexpression of the Androgen Receptor is the same as increased expression past the norm?
I know this is a basis of the theory on the homepage.

I could pull this line right here though,
“Increased androgen receptor (AR) expression and activity are pivotal for resistance to androgen-deprivation therapy.”

But then I see mention of gene silencing in PFS, which would mean reduced AR expression.
So is AR expression increased or reduced?
Increased AR expression seems it would be protective.
Anyone want to clear this up?

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#2

Increased AR “expression” and “density” are basically interchangeable. Sometimes people also use “sensitivity” to mean the same thing, although technically there is a very slight difference.

The theory is that our androgen levels and/or androgen output/products (proteins made when AR system works appropriately) drop after exposure to 5ari’s, anti-androgens, etc.

Our body then compensates by increasing the amount of receptors (ARs) in order to try to get more of the endproduct made (proteins).

When we stop taking the 5ari’s or antiandrogens or whatever caused the drop in AR, you get a tital wave of androgens back in the system while the system still has high ARs. This basically nukes the AR system (too many AR endproducts/proteins). In response (I’m guessing here but potentially to mitigate cancer risk among other things), our body then silences the AR in certain tissues by adding something like a methyl group (there are a few other “things” our body can add to silence) so that no matter how high or low androgens or ARs go, it sort of doesnt matter since the gene itself is now silenced. So no more/way less endproducts/proteins being made = PFS.

Now, how does that fit into people’s stories that got PFS while still taking finasteride? They didn’t stop the medicine and then have that tidal wave. It could be complicated interactions with other medications or even stress responses (i.e. Glutathione and allopregnenelone are severely affected).

So to answer your question, a silneced gene means no protein being made. No protein being made means our body is increasing AR in order to try to get protein made. For some reason, our gene(s) are stuck silenced. Some type of faulty mechanism not allowing it to de-methylate. CRISPR seems like the most likely treatment method, although there is a chance that in time, the gene(s) could re-methylate.

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#3

I’m one of those who had sides on fin (erection, penis size, mild brain fog) but they were not as bad as month off when I crashed.

#4

Thanks for taking the time on that.
Im still getting hung up on this part though, the AR gene is silenced (reduced expression) , but at the same time overexpressed (increased expression)?
Or one leads to the other?

#5

the AR gene is silenced (reduced expression) , but at the same time overexpressed (increased expression)?

The AR gene is silenced (reduced output) and expression (number of receptors) is increased.

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#6

Ok how about this. Maybe you’ve seen a few of my posts.
Lets start from scratch, not having taken any drug and no theories.

Again just a patent, maybe nothing to get too excited about, could be nothing.

Maintenance of male phenotypes
As a result of isolating vesicles derived from bacteria belonging to the genus Propionibacterium in vitro and evaluating therapeutic efficacy thereof, it was confirmed that the vesicles exhibited an anti-inflammatory effect and an effect of inhibiting the death of keratinocytes, and as a result of evaluating the mechanism of the vesicles, it was confirmed that the vesicles increased the expression of male hormone receptors

^Sounds good right?

Then apply the drugs, apply the theories.
Still good?
@moonman1

#7

Just to pivot here a little bit, this alone could be a big deal when looking at overall skin health and thickness. Not only that, but drug induced hair loss as well. Im thinking about Accutane here mainly.
Another “just in case”

“Protection from skin and hair follicle cell death.”

#8

I wonder do I have increased androgen receptor expression after I got so fucking hairy in my early teens after isotretinoin, despite having my androgen levels on the low side. Would that show in somewhere else?

#9

This is where I pulled that line from the patent.
“it was experimentally confirmed that, when vesicles isolated from in vitro cultured Propionibacterium acnes , which is one species of bacteria belonging to the genus Propionibacterium , was administered to mice, the expression of an androgen receptor in prostate tissues was increased”

^On the flipside of the coin, if the androgen receptor is overexpressed and thats a bad thing, bacteria might play a role in that too.

#10

Can you or someone help me out one more time here that knows the history or studies.
Are there some real world examples (meaning studies and such) that show this theory as a possibility?
Increased or overexpressed AR gene actually leading to a type of androgen deprivation?
Id check myself, but that doesnt seem like the simplest thing to find real quick.

#11

Yes, there are a few. But primarily one that showed increased AR in a part of the genitals.

> Differences in AR expression and nerve density in different portions of dermal prepuce were evaluated in the 2 groups. Density of nuclear AR in stromal and epithelial cells was higher in cases (mean 40.0%, and 80.6% of positive cells, respectively) than controls (mean 23.4%, and 65.0% of positive cells, respectively), P = 0.023 and P = 0.043, respectively. Conversely, percentage of vessel smooth muscle cells positive for AR and density of nerves were similar in the 2 groups. The ratio of AR positive stromal cells % to serum testosterone concentrations was 2-fold higher in cases than in controls (P = 0.001). Our findings revealed that modulation of local AR levels might be implicated in long-term side effects of finasteride use. This provides the first evidence of a molecular objective difference between patients with long-term adverse sexual effects after finasteride use versus drug untreated healthy controls in certain tissues.

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#12

Let me post this one here,

Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid

https://pubmed.ncbi.nlm.nih.gov/12457868/#:~:text=Proliferation%20of%20the%20lacrimal%20acinar,role%20in%20lacrimal%20gland%20function.

So are you trying to lower AR expression and cell proliferation?

The antagonistic influences of androgens and retinoic acid suggests that, under physiologic conditions there is a balance between the effects of androgens and retinoids in the lacrimal gland.
retinoic acid also completely inhibits androgen stimulation of cell proliferation.

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#13

The mice featured in the following study were engineered to grossly over-express AR in their muscle tissue. Androgens appear to have exerted a paradoxical effect on these mice.

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#14

Going back to that study,
“Androgens and retinoids are known to be involved in control of lacrimal gland function. Because retinoids generally antagonize androgen function it was the purpose of this study to investigate interactions of retinoic acid and androgens in rabbit lacrimal acinar cells in culture by determining effects of retinoic acid on androgen receptor (AR) mRNA expression, AR protein levels and androgen-stimulated cell proliferation.”

I could hit the stop button after that first sentence as I like to do.
Maybe now you only have two things to look at.
I could say it might not be all about the androgens when it comes to dry eyes or ocular health, far from it.

goblet cell RA may function in maintaining conjunctival immune tolerance and loss of conjunctival goblet cells may contribute to increased Th1 priming in dry eye.

It is well recognized that vitamin A is essential to maintain a healthy ocular surface. Systemic vitamin A deficiency is associated with loss of conjunctival goblet cells, hyperkeratinization of the ocular surface epithelium, inflammation, severe dry eye and increased risk of cornea ulceration ([19]. The lacrimal gland produces and secretes vitamin A, in the form of retinol into the tears . Expression of alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase, the enzymes that are required for the two-step oxidation of vitamin A (retinol) into the active metabolite RA, was previously reported in whole conjunctiva lysates
https://academic.oup.com/intimm/article/30/10/457/5052315

Intestinal epithelium , intestinal epithelial cell lines (;), and gastric ) epithelia have also been found to synthesize RA that can confer the ability to synthesize RA in bone marrow- and blood-derived APCs (. In the gut, retinol in the diet or secreted by the liver in bile is metabolized by RALDH1a1 in the small intestinal epithelium to RA that can be delivered to and condition tolerogenic properties in substantia propria APCs. We found the conjunctival goblet cells appear to have properties similar to the intestinal epithelium, in that they are capable of metabolizing vitamin A (retinol) that is secreted by the lacrimal gland into the tear fluid that bathes the ocular mucosa. Additionally, the conjunctiva goblet cells are similar to intestinal goblet cells in their ability to serve as passages for antigens from the mucosal surface to the underlying APCs where they can be delivered along with tolerizing factors, such as RA

These findings have potential implications for the conjunctiva by linking vitamin A secreted by the lacrimal gland to conjunctival goblet cells that are capable of conditioning adjacent APCs to maintain conjunctival immune tolerance and prevent damaging ocular surface inflammation, particularly in the context of disease related danger signals, like hyperosmolarity in dry eye ([Fig. 8](javascript:;)). Studies have found that ocular surface immune tolerance is disrupted in three different mouse models of dry eye

Going back to Accutane, it might not be Accutane itself that becomes highly toxic, but the buildup or lack of turnover of retinol or retinal.

#15

Going back to this, hypothetically (and this is based on the patents)
you have two major bacterias that are also early colonizers that could have somewhat of an antagonistic relationship.

Propionibacterium= increased Androgen Receptor expression (also might produce k2)
Bifidobacterium= decreased Androgen receptor expression (through the production of retinoic acid)

Both of these bacterias are capable of supporting the others growth.
Thats putting it extremely simple but there could be some truth there.

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#16

What do you guys think of this one?
Here it seems increased AR expression is a good thing for womens sexual health and that it declines with age, especially post menopause.
They also say Testostorne treatment to treat hyposexuality could be less effective with reduced AR expression. Reduced sensitivity to T treatment because of the lowered AR expression.
@Dubya_B

Androgen receptor expression in the human vagina under different physiological and treatment conditions

https://www.nature.com/articles/ijir201225

The physiological meaning of AR decline with age in the vaginal epithelium is unknown. T is known to regulate its own receptor in different tissues,24, 25 and the decline in AR expression in menopause may reflect the lower circulating androgen level. This decline of AR would render the menopausal vagina even more insensitive to the lower circulating T,2 and would explain the impaired sexual response of the menopausal vagina even in the presence of hormone replacement therapy.

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#17

It seems a decrease in AR is a common part of aging. Vaguely remember a similar study of men. This appears to be what happens under normal circumstances though. Nice that the importance of androgens for women is being studied more as time passes.

Having the volume turned too low to hear a song is similar enough to turning it up so high it blows out a speaker or fuse.

#18

“The decline in AR expression renders circulating Testosterone less effective as an androgen which would include TRT.”
To pull a thought from that last study.
Would it also be safe to say AR expression is increased during puberty?
Pulling a line from that patent again,

“when Propionibacterium acnes -derived vesicles were administered, an androgen receptor was overexpressed in the prostate tissue. It can be seen from phenomena in which an androgen receptor is stimulated for the treatment of breast cancer and atopic dermatitis is alleviated during puberty when the expression of an androgen receptor is increased that Propionibacterium acnes -derived vesicles exhibit therapeutic efficacy by increasing the expression of an androgen receptor, which is one of the therapeutic mechanisms. In addition, it may be anticipated that the overexpression of an androgen receptor is caused by protein components other than non-protein components such as PGN and LTA in Propionibacterium acnes -derived vesicles.”

^Do you want to stimulate AR or is it overly stimulated?

First things first are you trying to lower AR expression?
But not too much?

From how ive been looking at this, could Propionibacterium be a problem or solution?

#19

Maybe the most important statement in that article,

“These results raise the intriguing question of how a protein that typically promotes anabolic responses in muscle can result in atrophy and neurodegeneration when overexpressed. Whereas an answer to this question is not yet available…”

But again would you be trying to lower or better regulate AR expression in this case?

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#20

Going back to this, Part of its mechanism of action on prostate cells might include upregulation and activation of the Androgen Receptor. This was already shown in the patent Ive posted.

Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells

Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation.

IL-8 has been shown to increase the transcriptional activity of the androgen receptor in prostate cancer cell lines, suggesting a potential role of this chemokine in modulating the transition of prostate cancer to an androgen-independent state [35]. Other studies report that IL-8 contribution to prostate cell proliferation is independent of the androgen receptor [36]. Our data indicate that the prostate epithelium significantly contributes to locally increased levels of both IL-6 and IL-8 when infected with P. acnes , thus potentially promoting adverse effects as increased proliferation and angiogenic activities by autocrine and/or endocrine mechanisms. The pathogenesis of P. acnes in locations other than the hair-follicle is still poorly understood.

we demonstrate that prostate epithelial cells secrete inflammatory cytokines in response to P. acnes , partly through a TLR2-mediated mechanism. We propose that this strong immune-stimulating effect facilitates the bacterial colonization deeper into the prostate tissue where P. acnes can form long-lasting biofilm-like aggregates [7]. A possible mechanism may involve intracellular transport in recruited macrophages, as P. acnes has been demonstrated to withstand degradation by phagocytosing mononuclear cells [37].

Lets not call it an infection for a moment though, this is a very common and possibly important commensal from birth.

IL - 6 is an important mediator of fever and of the acute phase response. IL - 6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.