Also on neurosteroids normalising with SSRIs, I think you’re referring specifically to Fluoxetine which induces the 3A-HSD enzyme. This process comes after 5-AR reduction, so if there’s a blockade there it won’t help anything. I’ve tried both Etifoxine and low dose Fluoxetine with no improvement to speak of.
Yeah my level of progesterone was below the bottom
Of the scale. What does that mean in all this?
Seems that the next logical step is to test different combinations of compounds that decrease AR levels. When I spoke with Canada’s top androgen researcher, he agreed that this is a logical route. I have started compiling a list of these compounds, but its ultra tricky because many of them act as 5ar inhibitors as well, which we should avoid at all costs.
A PFSer has taken Zylamend in the past, and felt a brief recovery for about an hour which eventually went away, and he has not been able to replicate this expreience as now it just makes him “exhausted”. This is interesting because Zyflamend has been shown to decrease AR levels ( ncbi.nlm.nih.gov/pubmed/21958043 ), but also has many compounds in it that are 5ar inhibitors. If I can ever find the right time, I would like to do a component analysis and only take the compounds in Zyflamend that decrease AR levels without affecting 5ar enzyme activity.
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Moonman the researcher couldn’t recommend any known drugs that wouid serve the purpose.
Who is Canada’s top androgen researcher?
Fulvestrant decreases both estrogen and androgen receptors
What about increasing 5ar via protodioscin?
He mentioned Flutamide, although did not go as far to as recommend it (legal reasons).
Yeah top androgen researcher? Wonder what that means as well? We need a pathway specialist to identify where pathways may be messed up. I take it this is a new field with little research completed? baylor is trying to do this but we need more boots on the ground?
Flutamide is an anti-androgen. Stay away from that
Yes i agree regarding antidepressants. I would not recommend them at present due to possible worsening of sexual symptoms.
Taken from the PFS foundation site:
While the mechanisms of the sexual side-effects in humans is incompletely understood, one study found lower cerebrospinal fluid concentrations of dihydrotestosterone, progesterone, dihydroprogesterone and allopregnanolone, and higher levels of testosterone, 5α-androstane-3α,17β-diol and pregnenolone. Another study found up-regulation of the androgen receptor in the human foreskin with a mean of 5 years after finasteride discontinuation.
Interestingly 5 alpha reductase type 2 expression and transcription could be affected by progesterone. Admittedly this study is in females. By increasing progesterone it may be possible to increase the expression of 5 alpha reductase type 2.
ncbi.nlm.nih.gov/pubmed/11884637
I can’t seem to post my full post at the moment. Technical errors.
To note other studies show that in peripheral tissues such as the prostate and liver increasing testosterone increases 5 alpha reductase type 1 expression. So the effect on brain is different. Increasing progesterone should increase 5 alpha reductase type 2 expression and increase overall allopregnanolone.
It seems to me when we took finasteride a predominantly type 2 inhibitor (but also a type 3 inhibitor) we reduced DHT and overall allopregnanolone content. When we stopped it we have been left with low levels of progesterone and its metabolites as well as DHT. Also higher levels of testosterone and pregnenolone seem to indicate a lack of conversion to their metabolites through 5 alpha reductase. This seems to indicate 5 alpha reductase isn’t functioning correctly in the brain. This is likely local and not reflected in our serum results as some of us have normal or even high peripheral DHT levels.
If this is the case the question is why and by what mechanism?
The surprising find is the low progesterone content in CSF. Finasteride prevented the conversion to allopregnanolone but shouldn’t prevent pregnenolone converting to progesterone. Why this is i do not know. Could there be a problem with 3 beta hydroxysteroid dehydrogenase? Or more likely it is due to a problem with Human Steroid 5β-Reductase (AKR1D1).
ncbi.nlm.nih.gov/pmc/articles/PMC2740403/
It is possible in theory that by increasing testosterone further and progesterone we could increase 5 alpha reductase expression of the type 2 variety. Increasing testosterone would decrease allopreg as experienced by people who get worsening brain fog with androgens (like myself). Perhaps combining it with progesterone may help although this might simply just not allow testosterone to bind properly.
Another thing to be aware of is that some progesterone metabolites can inhibit both 5 alpha type 1 and type 2 and they can bind to the AR. When this happens progesterone turns into a negative tool. For this reason i think it is important to use progesterone carefully and not to over use it.
biolreprod.org/content/65/5/1378.long - this is in regards to tissues peripherally.
“Dihydrotestosterone not only binds to the androgen receptor but also increases gene expression of 5α-reductase type 2 by an autoregulatory mechanism, whereby increased testicular androgen production at puberty induces gene expression of 5αR1 and 5α-reductase type 2 in target tissues of androgen action [11]. Gene expression is further induced by dihydrotestosterone administration, thereby supporting an additional level of autoregulation. The regulation of steroid 5αR1, however, is not well characterized.”
“Although in some respects regulation of the type 1 enzyme by progesterone (P4) is similar to regulation of the type 2 enzyme by testosterone, significant differences exist, because 5α-dihydroprogesterone is not biologically active with respect to binding to the P4 receptor. Thus, at first glance, it seems paradoxical that progesterone may induce its own catabolism in P4-responsive tissues. However, metabolism of P4 by the sequential action of 5α-reductase and 3α-hydroxysteroid dehydrogenase leads to the formation of 5α,3α-hydroxy-dihydroprogesterone (allopregnanolone), which is a biologically active neurosteroid [12–14]. 5α-Reduced pregnanolones act predominantly through nongenomic mechanisms to alter cellular function.”
The above study is again admittedly in a female but it raises the question of whether progesterone can up regulate 5 alpha reductase type 1. Also important to note is that it argues in this instance that oestrogen is needed to help up regulate progesterone receptors and through which mediating an increase in 5 alpha reductase type 1 expression.
5 alpha reductase can also be induced by cortisol too. Increased 5a-reductase activity in patients with obesity and insulin resistance and have suggested that this represents a compensatory mechanism to increase cortisol clearance in an attempt to improve insulin sensitivity. Whilst i don’t think cortisol is directly affecting our problem keeping it low seems important to allow other substrates to bind.
Lastly the role of 5 alpha reductase type 3 is interesting. It helps with the conversion of polyphenol into dolichol as well as converting T to DHT and maintaining the androgen-androgen receptor activation pathway. It was only recently discovered and finasteride does inhibit it. In many tissues it is more highly expressed than type 1 and type 2. In the brain, eye and prostate if it does not function it can cause problems due to build up of its precursor and due to not being able to fold proteins such as asparagine residues which help in neuronal formation. Trynotoworry claimed a recovery from increased spinach intake (full of high dose dolichol). This is another area that should be looked into. There have been people who claim improvements with both spinach and asparagus. It could be part of a multifaceted problem. Whilst i think if it was completely cut off we would be much more severely unwell the possibility of a degree of down regulation is possible and gives credence to those who have had some success. I can’t find much info on how it is regulated but it is likely increasing testosterone and DHT would up regulate it also.
journals.plos.org/plosone/articl … ne.0028840
“However, in BPH-1-AR cells, which represent the transition between normal and cancerous prostate cells,testosterone could up-regulate the mRNA levels of all three 5α-reductase isoenzymes, which would result in high concentrations of DHT in these cells and further increase the expression of these isoenzymes. Such a positive-feedback loop is most likely to lead to constant activation of the AR, which at least partially explains the epidemiologic observation that a high concentration of testosterone level correlates with a high incidence of prostate tumor.”
The problems in the brain i believe are likely due to hormone production and enzyme expression whilst the problems with our androgens are likely more due to problems with the androgen receptor and AR signalling.
All i’ve wrote so far seems to say we should increase T and DHT to restore 5 alpha reductase expression in all tissues perhaps with progesterone to combat effects on allopreg.
The problem with that though is that there is a mechanism that operates then when testosterone and DHT increase they cause AR mRNA to increase. The auto regulation of AR is impaired. As the AR increases it becomes hypersensitive ncbi.nlm.nih.gov/pubmed/19808968 .
This may be the reason we end up in a silenced state as stopping finasteride leads to a rise in DHT. As DHT interacts with the receptor the output is seen as too much and other systems come into play to shut things down. So increasing androgens onto an overexpressed receptor might make things worse.
ncbi.nlm.nih.gov/pubmed/15212846
If the receptor is hypersensitive this might indeed be the cause of why androgens do not work properly - by silencing androgen responsive genes those post translational mechanisms as i mentioned earlier.
The brief success of androgen therapy followed by its wearing off would be explained by this.
Which mechanism is at play? I don’t know. Acetylation leads to up regulated recruitment of AREs. HAT inhibitors like rosacea, resveratrol, procyanidin B3, green tea, all spice, quercetin, and curcumin all inhibit acetylation in some way. How do people respond to these??? They should in theory make things worse. The other PTMs - methylation etc… are also possible.
If we understand how the AR is overexpressed we can work out how to reduce it back to normal levels. Now i think some of us have actually tried things that increase AR expression - such as vitamin D. Vit D in essence enhances cellular responses to androgens. In the short term increasing AR may be helpful but long term i think it may lead to more shut down. There might be other reasons why the AR is still overexpressed. Perhaps there is a structural problem with the AR receptor preventing ligands binding to it therefore it overexpresses as a compensatory mechanism. If this is so then high doses of androgens would be more useful and increasing the AR receptor.
Another problem is in determining what the helpful level of androgens is. For instance in some experiments show increasing androgens leads to increasing AR expression and others that it decreases. If upregulated AR is the cause of some of the shutdown then would this mean a low androgen status could be helpful if increasing androgens does lead to increased AR expression. This is risky. We know we have androgen deficient symptoms so the idea of decreasing androgens further seems counter intuitive. It seems to make sense that the influx of additional androgens could lead to worsening of symptoms if a post translational silencing mechanism is at play. There are many people who have used TRT or other testosterone boosters and had initial improvement due to increased activation of ARG. But a lot of these improvements do not stick or actually people get worse. Conversely some people actually report some improvements when decreasing androgens - even a few people who went back on finasteride (although this could also change the levels of AR again). It is unclear if testosterone is a positive or negative in terms of AR expression. If it does reduce AR mRNA then there could be some role for mild increases in androgen status. If it increases it then increasing it should be avoided.
Also the role of oestrogen needs to be considered. Increasing it can lead to up regulation of AR mRNA in the brain. Reducing it may lead to decreased AR mRNA expression as well as reduced progesterone receptors.
sciencedirect.com/science/ar … 8003002276
press.endocrine.org/doi/full/10. … .2004-0084
press.endocrine.org/doi/abs/10.1210/mend-4-1-22
ncbi.nlm.nih.gov/pubmed/1038 … t=Abstract
toxsci.oxfordjournals.org/conten … 7.abstract
physoc.org/47th-congress-of- … 20543PS243
Also tissue specific alterations from finasteride are possible. For example finasteride decreased the expression of epithelial androgen receptor in a tissue specific manner. Although we know AR is overexpressed in the penis it is possible this isn’t the case elsewhere.
ncbi.nlm.nih.gov/pmc/articles/PMC4137476/ - suggest finasteride decreases AR expression
onlinelibrary.wiley.com/doi/10.1 … ated=false - suggests it increases AR expression.
Overall it seems to me we need to:
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reduce AR expression. By which mechanism is uncertain. There are so many options. It is possible we need to choose the exact mechanism by which it is up regulated to bring out positive change. Choosing the wrong one might just make things worse. Increasing AR expression further for instance with increased oestrogen will make things worse. Reducing AR expression will make you feel worse as it will turn off some of the genes still turned on.
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Hopefully by doing this we slowly lift the silencing mechanisms that come thereafter. We might need to give them an extra nudge through medication or drugs.
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Increase testosterone and DHT when AR expression is reduced to increase expression of 5 alpha reductase particularly in the brain which is likely low. Also if silenced mechanisms and AR is decreased sufficiently then this should help drive the activation of ARGs. The risk of this is increasing AR expression further and reactivating silencing mechanisms. This step is unclear in whether its good or bad.
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Support neurosteroid production with progesterone which also helps increase 5 alpha reductase in the brain. Probably in short bursts as prolonged use leads to more negative genomic effects.
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Support dolichol synthesis with spinach and asparagus (just in case). Both are rich in vitamin A too which also drives down the AR.
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Reduce cortisol so it doesn’t get in the way.
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Reduce inflammation. Inflammatory cytokines contribute to raised AR receptor expression.
Only research can show us which path to really strike hard.
Please donate in either your time or money. This is a reversible process. But we cannot do any more without research.
People can get better. The way i see it is that we’re stuck in a well and sometimes with our efforts we climb up a little and then fall back down. Only research can show us the right way up. Some are deeper in the well than others to start with and have a more difficult climb and need some extra help. Why some people have positive reactions to testosterone i think depends on the degree of AR overexpression and the degree of the subsequent silencing. There’s a likely spectrum. It may well be we have to make our bodies crash through the use of potent anti androgen like casodex in order to reboot the system as it were but this is potentially dangerous and needs justifiable tangible evidence before considering.
This is solvable.
pfsfoundation.org/donate/
pfsfoundation.org/news/docto … h-studies/
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ncbi.nlm.nih.gov/pubmed/8499343
ncbi.nlm.nih.gov/pubmed/8495802
I mentioned oestrogen may increase Ar mRNA and AR expression in the brain.
Interesting the first article above seems to indicate testosterone should down regulate AR mRNA in castrated rats. So when androgens are removed AR appears to increase and then when testosterone returns AR expression decreases.
Testosterone when increased to high levels acted like DHT and increased in AR mRNA. When finasteride was used AR mRNA decreased as Ar mRNA was down regulated by testosterone alone. This happened due to increased conversion to oestrogen which was potent in decreasing AR mRNA levels. This goes against what happens in the brain where oestrogen likely increase AR expression!
That being said it is likely finasteride leads to increased AR mRNA - ncbi.nlm.nih.gov/pubmed/21557276.
Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirect effect mediated by a paracrine or endocrine mechanism elicited in another tissue.
The second study also shows that DHT is a positive modulator of AR levels increasing it. And that androgen depletion down regulated AR mRNA levels.
DHT is thought to be the androgen most helpful in erections. ncbi.nlm.nih.gov/pubmed/15146086
ncbi.nlm.nih.gov/pubmed/16422801
We need androgens to operate through the receptor and the ARGs to produce erections.
It is confusing whether increasing them or at least keeping them at the up border of normal is helpful or not in regards to AR expression. We want the AR to stop being hypersensitive. We need to decrease it. Ideally the PTMs would stop inhibiting ARG function at normal levels.
Then we need normal doses of DHT and T to bind with the receptor to activate it and the ARGs.
Some anti androgens could lead to increased AR expression and make things worse unless it specifically decreases AR expression.
Great thread. I wonder why it didn’t get more attention. Clearly in an effort to save our bodies, AR became hypersensitive to the level that increasing T does little to alleviate symptoms. I still think PFS is primarily neurological and that the Italians are our best hope for cracking this code, but wonder why more attention hasn’t been focused on reducing androgens to see if that wouid help reduce sensitivity. But I’ve only been on this forum for a few months. Have folks taken anti androgen drugs to attempt this or is this still quite theoretical with a lot of potential downside?
I am curious to hear peoples reactions to: selenium, DIM, and milk thistle.
I know awor had a bad reaction to milk thistle.
All three reduce androgen receptor expression.
And resveratrol.
We know from this study: ncbi.nlm.nih.gov/m/pubmed/24959691/ that we have increased amounts of AR in epithelial cells and stromal cells.
The impact these things could have could be either beneficial or detrimental. If you’ve had experiences with each please let me know.
A good trial would be someone on TRT going without an injection for 4 weeks. Then slowly reintroduce testosterone from a small dose.
Been thinking of this for a while but need to get significant time off work to try.
Great thread. I just crashed and my exams did show high level of progesterone and dhea, aswell as cortisol. I really think that we are getting closer to a possible treatment. The best part is that these findings are going to help a ton of men, not just pfs suffered.
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Many guys tried to go on and off trt with no success. Also many guys here have low T and high E, myself included. I’m too brain fogged to understand all the science talk, but doesn’t that kind of go against this theory?
19 … absolutely great thread. people should be really be reading this. Send me a pm pls