Androgen receptor (AR) overexpression and sensitivity to hormones reversed by epigenetic therapy that restores Purα to a transcriptional repressor complex (RC) of AR deregulated in hormone refractory prostate cancer (HRPC) | Journal of Clinical Oncology

https://ascopubs.org/doi/abs/10.1200/jco.2008.26.15_suppl.5065

If our problem is AR insensitivity to testosterone HDACI-bicalutamide could be the solution.

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This seems big for us

Published in 2016. Wonder if the real science guys on here have read this. I barely can read at this level of science. @axolotl @awor

If we had a rat model with our genetics and pfs then we could try these things out.

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I posted about this a while back, here

and here:

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Thanks for the response. @awor !

hey @Shellnyce,

Not specifically this but we’ve read a lot regarding vorinostat and pabinostat which seem to be what is in use here, including the following more recently:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324663/

As awor points out we’re aware of these and they are of interest to us.

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What’s the conclusion drawn for this? The first thread alone has 600 replies

Hey @axolotl ,

I know you have mentioned in passing that you may have a paper your working on. I feel like there is so much info that is narrowing down on many of the mechanisms at work here. I cant wait to see what your working on. We appreciate your efforts!

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As I wrote, I tried valproate. Unfortunately it made me worse. However, it may be that valproate targets the wrong HDAC’s, there are quite a few different ones. I still believe there may be a chance, that some HDACi may help. The problem is, that some of those HDACi’s are also quite cytotoxic. In any case, I feel that it’s worth keeping an eye on the subject.

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I appreciate the response. Not to hop back on the Baylor hype train but would any of the findings possibly shed light on which HDACs we want to try to target? From reading some of your updates, while you weren’t cured, it did seem this treatment gave you some relief at first which seems promising

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Having some data on which genes are deregulated in this mess, would certainly help a lot. Otherwise, it’s like being in a huge unknown city, without speaking the language, and no map. That is why I wanted that study done in the first place.

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can someone please explain how does one pill cause epigenetic changes for some people here. or how does epigenetic change explain crashes that people experience?
while other people feel nothing when they take this drug for years and one guy gets epigenetic change?

I an sorry I don’t understand this. please someone give me explanation any kind if it isn’t too much to ask.

thank you in advance.

Why has no one tried aza or deca, the two demethylating agents? I think there is a high chance a lot of gene silencing is causing our problems. I know its risky, but people are commiting suicide over this condition. Things like valproate don’t effect even a percentage of things like these two agents. Honoustly interested.

Zadig, rest his soul, and I believe another PSSD forum member, supposedly acquired azacitidine but there seemed to be no report on the effect it had for either of them.

Does anyone know if it was actually trialed among any PSSD patients?

I am deeply into this stuff, even trying to make an appointment with a doc in india to do it on me. Zadig didn’t do it, he wanted to, but never did it. There was a report on pfs from a guy claiming he knew another guy that tried it for 4 days, got ill, and quit. The guy could get drunk after these 4 days again. He said this guy tried aza, which doesnt cross the blood brain barrier, deca does. And also he did it only 4 days, and the real demethylation takes place the 2nd cycle, so the 2nd 4 days (u cycle 4 days with a week in between). On the pssd forum no one has tried, I have pssd and read the forums there. I just find it unusual no one has tried it yet while people are commiting suicide. On the other hand its extremey hard to get, so I understand. I think it’s very promising, especially knowing methyl donors worsen us. I also found an artical talking about epigenetic changes taking place after drugs use/during withdrawal, this happened to me too. "Co-author Fal Yadid, of Bar Ilan University, added:

'Surprisingly, we discovered that the biggest changes in DNA methylation occurred not during the exposure to the drug but during withdrawal.
'During this period of withdrawal, hundreds of genes changed their state of DNA methylation including genes that were known before to be involved in addiction."

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Thanks for the report. I was under the false impression that at least a couple PSSD patients had tried it. My fear is that to achieve a strong enough effect to reverse this condition, it may require an intolerable toxic dose.

There were also a couple reports of PSSD patients using valproate for its epigenetic effects. I believe one claimed recovery and another said it made some symptoms worse?

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well i found out that lower dose decitabine, so not high, is the best for demethylating genes. Going higher is even worse for demethylating as weird as it may sound. The only worries i have is that not all genes are effected good enough by the deca. On the other hand a guy on the pssd forum told me deca has been showed to be able to unsilence the dopa pathway, and Androgen genes. There is a guy who tried a combo of demethylating ‘‘agents’’ like valproate and some other stuff on the pssd forum, to mimic the effects of decitabine. Supossedly there is a pubmed article where they say they give this combo to cancer patients who don’t tollerate the real deal (deca) well. Another pubmed article claimed this combo doesnt even come close to the demethylating effects of deca. He said it recovered him for 60 percent, so that’s something.

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With aza I suppose you are referring to 5-aza-2’-deoxycytidine, which is Decitabine. What did you mean with “deca”? Btw, there are many substances that have been shown to be demethylating agents, not just two. So which ones do you try? I tried this one (IV procaine).

Most things in our body are highly conserved over millions of years of evolution, and here for a purpose. The whole methyl group system, comprised of methylation and demethylation processes, is absolutely essential for life. For example, methylation plays a key role during cell mitosis (cell division). If you start interfering with those processes too strongly or in the wrong way, you’ll likely quickly end up dead.

The big problem with demethylating agents such Decitabine, is that they are very powerful and unspecific, meaning they will act all over, also where we don’t want them to (which is in most places). Once we find out what to do, we will hopefully only want to target a few specific sites. CRISPR type approaches are more promising here. On the other hand we also have HDACi’s, which is what the article posted in this topic is about. There are many of those too, and some will only target specific HDAC classes, which is a little more specific, but still not great either.

Epigenetic changes can happen very quickly. I would guess that we are all genetically predisposed to a certain degree. Because of the highly variable nature of our syndrome, in genetics the phenotype of “PFS” (etc.) would likely be classified as what is called a “continous trait” (also known as a quantitative trait). A continuous trait is controlled by multiple genes. This would mean that multiple genes, in various dominant/recessive combinations, are predicting our syndrome. I very much hope that we will eventually get at least some hints in that direction from our GWAS research project. The continous nature would explain why some guys get it very mildly after a long time, while others get an extreme form after only one or few pills.

Very high level, I believe that the basic mechanism is as follows:

  1. Anti-androgenic action at the cell level causes an upregulation of the AR and induces epigenetic processes which keep AR-overexpression persistent
  2. Overexpression of AR and ARG’s (Androgen Responsive Genes) causes negative regulatory response, thereby silencing signals
  3. Withdrawl of substance causes increase of AR activation, thereby exacerbating processes described in previous step. This is what we would call the “crash”
  4. AR remains in persistent state of overexpression, whereby further increases of androgenic action worsen the symptoms, while antiandrogenic influence will at least transiently improve the condition.

This hypothesis is supported by findings in the Di Loreto paper below and the basic underlying mechanisms of the above hypothesis have recently become quite well established in various publications. @axolotl, who unfortunately is very ill at this time, has been working on a comprehensive literature review in this regard.

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Is the problem in the pssd guys also in the AR receptor?

If SSRIs mess with serotonine, which can also cause sexual dysfunction, could it be possible that serotonine receptors or serotonine levels in the brain played a role in their case?

Sorry, I am not a science guy, so I may be asking a stupid question without even knowing it. But this is a doubt that I have been having for some days.

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