Opinion on AR overexpression

General Discussion
#1

Hey people. I told mesolimbo the common believe on this forum is, that u guys think u suffer from AR overexpression. He said this:

It’s possible that they have misinterpreted studies relative to AR expression. These studies show that AR over-expression is tissue-specific, mostly along the human foreskin (stromal and epithelial cells) as well as the cortical regions. Androgen receptors in the normal prostate can be downregulated by Finasteride, while upregulated in the hyperplastic prostate. [link][link2]

When it comes to neural AR expression, androgens can upregulate them while Finasteride can partially block this effect, except for cortical neurons. [link3][link4]

In the penis smooth muscles (not foreskin), T and DHT actually upregulate AR expression. Only when 5-alpha reductase is blocked does testosterone downregulate AR there (through aromatization to estradiol)
[link5].

Finally, it’s important to determine which cell types are affected by Finasteride-induced AR over-expression instead of generalizing this to all tissue types. It’s also important to take into consideration auto-regulation and cross-regulation of nuclear receptors, especially the interaction between estrogen and androgen receptors (and different interactions across different cell types)

What do u guys think about this? @Dubya_B @axolotl @awor

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#2

When 5ar is blocked it doesn’t aromatize T to estrogen…

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#3

Hey, I thought I was the one who told him that, first at least ( lol :smiley: )

Btw I thought the same to ask You guys here on forum the same, because Mesolimbo is our very knowledgeable and exceptionally smart member, maybe even some collaboration between You guys and him would be very fruitful

For You to get a full picture of what he said, before telling him that overexpression of AR is more or less the most common theory here, I first asked him about PSSD and PFS connection

Reply to my question, quote from Mesolimbo
"I think PSSD and PFS have a couple of pathways in common, but not everything overlaps. For example, in both conditions neurosteroid synthesis is disrupted through either inhibition that seems permanent (PFS) or tolerance to their effect after long-term potentiation (PSSD). I talked a bit about this in my allopregnanolone article:

Androgen receptors upregulate in presence of androgens, as such androgens are potent regulators of their very own receptors. When you take Finasteride, you are significantly reducing DHT, so I would expect that AR expression would also be reduced. Perhaps that’s why some PFS sufferers found relief on tribulus terrestris - since it upregulates AR expression a little. Another way to upregulate AR is through TRT that puts your testosterone along the upper limit. After several months, AR expression would be elevated.

So, an important similarity between PSSD and PFS is how elevated serotonin can depress androgen receptor (AR) expression directly. Some SSRIs also lower testosterone through non-serotonergic pathways (i.e. Sertraline, Venlafaxine), so you end up with reduced androgens (even if temporarily) and reduced AR expression. I find PSSD more complex though, since many other pathways are affected. I’ll go more in-depth in my next article."

#4

haha said it just after you I see.

#5

I don’t think it’s accurate to say this is the common belief on this forum. We have not really discussed the matter in much detail beyond the site staff and I don’t feel the concepts are broadly understood. I will say that Awor publicly predicted deregulation of the AR and a consequent significant loss of neurosteroids in 2010.

I didn’t read all of this because I don’t have much time but I am confused by the suggestion “Finasteride can partially block this effect” when the study they cite for this point plainly says this:

In males given T plus FIN, a condition in which 5areductase activity was blocked, increases in AR at the 7-h time point were comparable to those seen with T and DHT alone. This indicates that T up-regulates AR as effectively as DHT, at least within this time frame.

That is notedly not blocking the effect. While I appreciate he appended “except cortical neurons”, nothing else in those studies is at all relevant to his sentence, so why are those studies linked at all? I find acontextual study linking is a big source of confusion to others and invariably a waste of time. I’ve just wasted five minutes looking through completely irrelevant studies. This does not give a good impression.

Regardless of what anyone expects, finasteride induces a persistent upregulation of the AR in the cerebral cortex of sub-chronically treated rats. This was an important finding of Giatti et al and involved Roberto Melcangi. The expression of AR was highest at the final period of washout.

As shown in figure 2 a, after finasteride treatment, we observed a significant upregulation of AR protein levels in the cerebral cortex.

As shown in figure 3 , at the end of the withdrawal period, the protein levels of AR ( fig. 3 a) and
ERα ( fig. 3 c) were upregulated in the cerebral cortex

This is simply the normal physiological response. It’s important to note that PFS is an aberrant response.

AR expression is significantly increased in symptomatic tissue in PFS, and a key reality we have been telling people endlessly is that while antiandrogens often relieve symptoms in PFS, sometimes transformatively, they can be extremely dangerous and have preceded further crashes and suicide. People often ask for significant warnings to be placed on the forum because of this.

Di Loreto et al. reported 2x AR expression vs controls across measured cell lines in PFS patients with penile atrophy and pain averagely 5 years after cessation. La Marra, co-author of the study, expanded on this in his thesis noting the following:

The percentages of AR positive cells are always higher in the cases than in the controls. Statistical analysis showed positive correlations between:

  • The increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS
  • The increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion
  • The increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” (per AMS)

Of course, CRPC is the most well studied cellular adaptation to androgen deprivation, and histone modifications occur following an initial downregulation that significantly and persistently increase AR expression as a result. It is highly unlikely this adaptive mechanism is cancer specific and upregulation in response to low androgens can be demonstrated elsewhere in nature.

With regards to the effect of serotonin on the AR, I’ve written about this in detail already here.

The regulation of the AR is complex, tissue-specific, and responses strictly depend on epigenetic status. @Awor and I are putting together relevant information and will seek to publish it in some form.

I would suggest as always that anyone with ideas they think are credible take them to a scientist in an appropriate field for feedback.

Best

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#6

I think what u said about us not getting normal reactions is important in this all. Trying to think of what normal responses are and applying that to our states may not work, since we obviously didn’t get the normal response.

#7

His reaction:

AnhedonicApe wrote:I didn’t read all of this because I don’t have much time but I am confused by the suggestion “Finasteride can partially block this effect” when the study they cite for this point plainly says this:

In males given T plus FIN, a condition in which 5areductase activity was blocked, increases in AR at the 7-h time point were comparable to those seen with T and DHT alone. This indicates that T up-regulates AR as effectively as DHT, at least within this time frame.

That is notedly not blocking the effect.

The study also noted:
Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR

AnhedonicApe wrote:While I appreciate he appended “except cortical neurons”, nothing else in those studies is at all relevant to his sentence, so why are those studies linked at all? I find acontextual study linking is a big source of confusion to others and invariably a waste of time. I’ve just wasted five minutes looking through completely irrelevant studies. This does not give a good impression.

Sorry for the confusion. Since I mentioned the cortical region in the opening statement, I wrote it again to remind the reader that these two studies that I linked regarding neuronal AR exclude this region.

I’m also short on time, so I don’t provide reference links to everything I post on the forum since it’s too time-consuming. However, if a member wants to confirm something I said, they can for example literally search for “androgen receptor cortex finasteride pubmed” and it’s the first result of the search. It takes less than 1 minute.

AnhedonicApe wrote:’‘When you take Finasteride, you are significantly reducing DHT, so I would expect that AR expression would also be reduced.’’

Regardless of what anyone expects, finasteride induces a persistent upregulation of the AR in the cerebral cortex of sub-chronically treated rats. This was an important finding of Giatti et al and involved Roberto Melcangi. The expression of AR was highest at the final period of washout.

This is simply the normal physiological response. It’s important to note that PFS is an aberrant response.

What I’m pointing out that although AR upregulation is found in some tissue types, AR downregulation is also found in others. My point is: since the burden of evidence falls upon the research reviewer, it’s important to look into all angles relative to the topic at hand.

In this particular case, the cerebral cortex isn’t the only tissue type or region in the body. As I mentioned before, in the penis smooth muscles, T and DHT actually upregulate AR expression. In the normal prostate, Finasteride also downregulates AR expression. These are also important symptomatic tissue in PFS, aren’t they?

To clear the misunderstanding regarding AR expression, they should also research nuclear receptors auto-regulation and cross-regulation. For example, estrogen receptor activation can regulate the expression of both androgen receptors and progesterone receptors. This is also tissue-specific, causing downregulation in some tissues and upregulation in others. It’s important to find symptomatic relief options for PSF - or even a cure.

PSF deserves more in-depth look into the different angles. It’s a complex condition.

AnhedonicApe wrote:Di Loreto et al. reported 2x AR expression vs controls across measured cell lines in PFS patients with penile atrophy and pain averagely 5 years after cessation. La Marra, co-author of the study, expanded on this in his thesis noting the following:

''The percentages of AR positive cells are always higher in the cases than in the controls. Statistical analysis showed positive correlations between:

The increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS
The increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion
The increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” (per AMS)
Of course, CRPC is the most well studied cellular adaptation to androgen deprivation, and histone modifications occur following an initial downregulation that significantly and persistently increase AR expression as a result. It is highly unlikely this adaptive mechanism is cancer specific and upregulation in response to low androgens can be demonstrated elsewhere in nature.’’

If that’s indeed the root cause of PFS, then wouldn’t chronic supraphysiological TRT downregulate the receptors and be essentially a cure after chronic use, if androgens generally downregulate AR expression?

AnhedonicApe wrote:The regulation of the AR is complex, tissue-specific, and responses strictly depend on epigenetic status.

I would suggest as always that anyone with ideas they think are credible take them to a scientist in an appropriate field for feedback.

Although PFS research review is not my main focus, what I wanted to highlight is the misunderstanding of AR over-expression being generalized. Even in tissue types that are also relevant to PFS symptoms, the opposite effect on AR expression can be seen. One should also take into consideration the cross-regulation of nuclear receptors.

#9

Can you give him awors 2010 paper for review?

#10

Yeah i linked it in the thread, but I don’t know if he will take the time to read it.

#11

Maybe ask him directly if he would be so kind to review the paper. Maybe he is able to poke some holes in it. We would appreciate it.

#12

I will ask him again

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#13

Erm, within a paragraph of saying to go and search on pubmed for proof of what he’s saying, he is then saying the burden of proof is on the literature reviewer. I’ll go with the latter of this contradiction.

Apologies if this is this week’s guru, but we don’t have time to follow users down all their rabbit holes. He is apologising for an absence of citations - I just explained he did provide citations, and they had nothing to do with what he said. As the segment he’s pasted shows, they do not support what he said.

Furthermore I am absolutely baffled as to what is going on here considering neither this person, nor anyone, has any idea what our understanding entails and what we are working on. I can say suggestion of involvement in the pathology has been produced in primary research of PFS (Di Loreto) and subsequent literature review (Traish 2018, Than 2018). Traish is a renowned expert on steroid signaling.

It’s not really practical to have such conversations on forums for this reason as quickly such “discussions” become large walls of text with no coherent point. Arguing the minutiae about reports of AR regulation is completely pointless outside of a context of why this is relevant, with someone who obviously isn’t aware of why that is. The answer to his question regarding TRT is no. As I’ve mentioned tissue response is strictly determined by epigenetic status.

We are very aware AR regulation is tissue specific as I specifically mentioned. I am quite aware “PSF” is complex. I would simply suggest to be careful if this is someone offering treatments. At a guess I would suppose that’s the case.

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#14

In your first response which you deleted you said his response was enlightening. Did you change your mind?

#15

Yeah he is not offering treatments, more advice to people. He is considered the ´´smart guy´´ on the PSSD forums, people often ask him for advice etc. He is a pharmacologist in real life.

#16

I changed my mind about being sarcastic, yes, in case it was misinterpreted that way :smile:

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#17

So he is claiming that research shows that finasteride produces AR overexpression in some PFS relevant tissue but AR underexpression in other PFS relevant sites…

#18

Mesolimbos first comment on the paper:

I’ve read the paper. Interesting ideas and much work went into writing this paper, it’s respectable.

Before commenting on the content I must conduct my own research review on PFS. I haven’t looked much into PFS since it isn’t my main focus, so I’ll set aside some time for researching PFS after writing my article on libido.

Perhaps the discrepancy that caught my attention the most is the bit about conciliating AR hypersensitivity with LH downregulation in the light of silenced AR signal.

If I understand this correctly, they say that nuclear AR is over-expressed and silenced on peripheral tissues. The hypothalamus, on the other hand, avoids this abnormal auto-regulatory effect. This is explained by the presence of a membrane-bound AR on the hypothalamus. The problem I see with this argument is assuming that membrane-associated AR are present on the hypothalamus alone, allowing it to have a different auto-regulatory process compared to other tissue types.

This is contrary to the fact that membrane-associated ARs are present on a wide variety of tissue types, including on the reproductive, cardiovascular, immune and musculoskeletal systems. [1][2][3][4][5]

I’ll comment more on the paper when I review the studies on my own and think about other mechanisms in mind.

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#19

Hello @AnhedonicApe and @axolotl I recently encountered this article about “ Overexpression of Androgen Receptors in Target Musculature Confers Androgen Sensitivity to Motoneuron Dendrites “

https://academic.oup.com/endo/article/152/2/639/2457023

In this article they found that over-expressed AR’s causes shortened and thickened neuron dendrites and they give a reference to some other paper about erectile function. It was about sexually dimorphic motor nucleus that controls penile reflexes involved with copulation.
May be this how pfs effects it seems worth checking for.

Hypertrophy of dendrites in HSA-AR Tg males
Although the androgen sensitivity that was induced in the dendrites of quadriceps motoneurons in HSA-AR Tg males resembles what has been reported in other, normally highly steroid-sensitive motoneuron populations (36–38), there is an interesting difference. Dendritic lengths in HSA-AR Tg males with circulating androgens (the sham males and castrates treated with testosterone) were substantially longer than those of WT males, and castration of HSA-AR Tg males reduced dendritic lengths to levels similar to those of WT males. Thus, overexpression of AR in the target musculature produced hypertrophy of quadriceps motoneuron dendritic length whose support required testosterone. This hypertrophy could have functional consequences. For example, reductions in the length of quadriceps motoneuron dendrites results in marked reductions in stimulation-evoked motor nerve activity (55). In SNB motoneurons, animals with longer dendrites have a greater percentage of intense erections and a greater number of reflex clusters (81). It would be interesting to assess whether the hypertrophy that we observed in the quadriceps motoneuron dendrites of HSA-AR Tg males might result in altered motor function, for example, producing greater force generation at the muscle.

It is like increased AR positively effects muscle performance but at the same time it negatively effects erectile function…

A new theory about why PFS happens