Reversing silenced AR signal with demethylating agents - A promising treatment option?


#461

@Frustrated

No, you misunderstand what I said completely. I am not arguing PFS exists. PFS has destroyed my life, so why would on Earth would I argue its existence? Also, you did not include a portion of my quote so it is taken out of context the way you present it.

I am saying that there is little to no value in people trying to say what the mechanisms of PFS are and what certain symptoms or blood values mean etc. because none of us have any answers, whatsoever, no matter how badly we want to, and no matter how many studies etc. we read and try to use to connect the dots. People should discuss their conditins etc., but there is no way people here can claim anything such as “definitve proof” when it comes to the mechanisms etc. of PFS. Not yet anyways.

Anyways, you guys can debate and create theories and try to apply certain studies and rules to PFS if it makes you happy, even if people are simply trying to blindly interpret research results … it is no concern of mine anymore.

Good luck to all.


#462

talking about theories and being not a researcher is a waste of time

pure metaphisic

we r waiting a definitive “sign” that put us in the pfs category

a bunch of symptoms is not sufficient

these signs r some kind of genetic predisposition (probably) and other stuff

we can just wait


#463

Has this paper been discussed here?

ncbi.nlm.nih.gov/pubmed/16079795

LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.

Abstract

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.


#464

“Sulforaphane” has been found to work both as a HDAC inhibitor and also a promoter of de-methylization (specifically in at least prostate cells).

Here is a Sulforaphane product…
physicianformulas.com/store/scripts/prodview.asp?idproduct=267

Anna Hsu, Carmen P Wong, Zhen Yu, David E Williams, Roderick H Dashwood, Emily Ho. Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells. Clinical Epigenetics, 2011; 3 (1): 3

clinicalepigeneticsjournal.com/content/pdf/1868-7083-3-3.pdf

sciencedaily.com/releases/2012/02/120228140555.htm


#465

Have you tried this?


#466

No, but it is on my long list of things to try along with SARMs.


#467

Ok i just want to give you guys a list of dietary epigenetic agents:

Curcumin
Sulforaphane in broccoli
Genistein - in soy
EGCG in green tea
Resveratrol
Selenium
DHA
Chlorogenic and caffeic acid in coffee
Allspice
Procyandin

Now nearly all of these things reduce the activity of the androgen receptor whether by its HDAC inhibition or decreased HAT activity. If you don’t believe the androgen receptor is affected i recommend you load up on green tea as i did and see what happens. My experience after drinking about 2 and a half litres of it for 3 days was a complete crash in every aspect including sexual libido, erections, size, stopped sweating, worsened sleep etc… This also however included a complete removal of all prostatic discomfort. Resveratrol (increases testosterone, decreases AR) i find improves some things but worsens other things particularly vision and fatigue when i take it.

There is also alot of misunderstanding of what awor is saying. He is saying there is a problem somewhere between the androgen receptor and the androgen responsive genes. He is not saying the androgen receptor is downregulated. If anything its the opposite. Somewhere along the way the AR signal is altered in such a way that not all ARGs produce adequate amounts of protein. Therefore he and the research team are thinking along the lines of epigenetics. Now this doesn’t mean that all ARGs are switched off as many of us do display androgenic features which increase when we supplement or boost hormones. However, this sort of supplementing might boost some activity whilst diminishing other activity.

I recommend people to read the book “the Epigenetic Revolution” by Nessa Carey. It summarises the field as it is known as of yet. There is a lot more to figure out in this field. This is illustrated by the fact that most research articles in this field were only released in the last year or so.

Basically what happens in a cell is that the hormone binds to a receptor. They stay together and enter the nucleus. They bind to DNA - A, C, G, T bases found at the promoter of certain genes. This switches on genes. Now when it binds to the these epigenetic enzymes are attracted which alter the histones, removing markers that repress gene activation and putting on marks that activate genes. If there is a change in these epigenetics then some genes will not be activated.

Now there are many epigenetic mechanisms. DNA methylation is the most widely studied and is thought to be the most permanent type although emerging evidence is starting to suggest that it isn’t always. Prolonged changes in HDAC activity might lead to a more permanent change via DNA methylation. There are different types of HDAC which do different things for example butyrate increases AR expression whilst sulforaphane reduces it. But there also other mechanisms such as sumoylation, phosphorylation etc… Also the role of miRNAs and ncRNAs is undetermined as of yet in the scheme of things. One thing seems likely and thats they are interwoven with each other. The point is no one is an expert yet in this field. We simply do not know enough.

The research awor is organising will give us answers. We can theorise all we want but only two things can help us. One is the research and the other is in the trying of remedies and the collection of data on the effects they have on us. After all thats how we got this far.


#468

excellent summary :slight_smile:


#469

Yes! One big thing is the research. The other is like you said. We need a big collection and data, that will show us a clinical direction. We are working on that. All of you here can help.
First Step:
making a big summary of all natural treatments.
viewtopic.php?f=6&t=6655
next step: A big web based poll, that will give us a very good overview by the data.
next step: Hormonal treatments and so on.


#470

Ok i did a 6 day treatment using the demethylating agent lidocaine whilst subsequently reducing AR via the use of green tea, milk thistle, soy, selenium, oligonol, antihistamine, sulforaphane and quercetin. I initially included curcumin as well but i felt this had more negative effects.

I took the androgen receptor reducing agents for 2 days before starting lidocaine and it pretty much as anticipated induced a crash. I speculate that an overexpressed AR is giving us what little function we have so reducing it would precipitate a crash.

I then took lidocaine in an increasing dose intravenously under supervision (15min readings of BP,pulse, ECG). During which i noted similar feelings i get to when i increase testosterone - mainly an uncomfortable feeling around the eyes. As i increased the dose this feeling became more pronounced. Awor and procaine had a similar reaction and initially worsened on it. He thought perhaps this was due to a reduction in hypersensitivity leading to a feedback effect causing more LH and FSH to be produced increasing testosterone leading to downregulation of the mechanisms past the receptor.

Now after therapy which ended a week ago i continued to take AR reducing agents which still make me feel not so good. I have not had visible improvements.

One thing to note is that by reducing AR i nearly completely remove all prostatic pains and numbness. However, function deteriorates with it.

My next plan is to continue reducing AR but also try and alter the downregulated mechanisms. Now i don’t know the mechanism and only research can tell us but for now i am going to assume that p300 is a good candidate to mess with for the reasons below. Now this is one of many things that could be affected so this is very much a guess. But my reasons are:

  1. p300 activates via its HAT activity about 40% of ARGs. It does not activate the AR gene as keep in mind the AR gene is an androgen responsive gene. Therefore if it is downregulated it makes sense that AR is not.

  2. p300 is upregulated in times of androgen deprivation to maintain things.

  3. p300 is downregulated by testosterone. This explains why to me that testosterone supplementation (or increasing it like i did via tribulus and resveratrol) improves somethings in myself and worsens other things. The other 60% are driven whilst 40% are shut up even more.

  4. p300 is upregulated by dexamethasone and sepsis. A few cases of acute ill health have told stories of temporary recoveries. A few people have had success on dexamethasone. As it is a nuclear co-activator it interacts with glucocorticoids and thyroid hormone. Therefore by increasing these it might be possible to increase expression. In fact benefits from long term low dose of these two might affect us.

  5. p300 is modulated by retinoic acid. Remember tryingnottoworry had a complete recovery on spinach of all things! Now he believed his dolichol hypothesis but that doesn’t carry much weight in my opinion now. I believe his story to be genuine and spinach is full of vitamin A. Vitamin A can modulate p300 activity.

  6. Personal trials of Ar reducing agents and p300 reducing agents. For example whenever i get downregulation of whatever it is downstream i get this strange feeling between my eyes. I got it when i took tribulus, when i took resveratrol and when i took curcumin. Curcumin downregulates AR but it also downregulates p300. Resveratrol downregulates p300 and testosterone does too. I do not get that feeling if i take other AR reducing agents. Coincidence?

The problem if this is true is that if we reduce AR - most of the things also seem to reduce p300. If we upregulate p300 an overexpressed AR would potentially shut its expression off again. So we need to concurrently find a way to downregulate AR whilst upregulating p300.

Now depending on severity of downregulation one agent such as dexamethasone might not be enough to sort things out. Maybe by combining them one has a chance. Mitch used armour thyroid, and isocort and improved eventually. Cytochrome had one recovery via Dexamethasone but then it didn’t work the second time. Dury had some success with synthyroid. Tryingnottoworry and his spinach experiment. Also other stories of temporary recoveries in times of illness, in times of using tyrosine and iodine lend a little credence to this.

I don’t know if this idea is true but i’m going to test it out.


#471

Keep going and good findings!!!


#472

Ok i stopped everything a few days ago and thought I would see what would happen if i provoked my p300 idea by taking very high concentrations of apple polyphenols including procyanidin.

ncbi.nlm.nih.gov/pubmed/20955177

It really hit me hard. Harder than some of the other things that reduce AR. Shrinkage, fatigue, and I got the same eye symptoms I get whenever i increase testosterone (tribulus, resveratrol).

I only took it for 2 days. Stopped it now and its told me enough.


#473

Hi 19,

please could you tell me more aboubt "One thing to note is that by reducing AR i nearly completely remove all prostatic pains and numbness. However, function deteriorates with " specificly the numbness. What was it like before and whilst reducing AR.

Thanks


#474

What i meant was reducing AR got rid of my prostate pains and the numbness referred to perineal numbness not genital numbness. I had soem shrinkage and less full erections if i got them.

Before i had prostate pains which could be quite crippling. This is not an issue now but fatigue is still not good.


#475

do u suffer from genital numbess at all? and if so did this improve


#476

Genital numbness for me improved when i was on doxycycline. it is still not quite right but its better than it once was. I still have off days though. reducing AR didn’t really make this aspect much worse for me.


#477

Has anyone seen any information like this before? Anyone been on any of these and can report on it?

It goes on to say the following symptoms were cleared up:

drmyhill.co.uk/wiki/CFS_-_The_Methylation_Cycle


#478

This supplement works along that theory – healthy-living.org/html/methylate_me.html


#479

Bryce,

Great find. Dr Myhill is a UK based doctor. She is one that at some point i want to engage with. Even though she has been attacked by the general medical community here, she seems like she would be the most useful to us from a treatment perspective, because she is a bit more leftfield, is prepared to think outside the box and entertains things like CFS with an open mind. She is prepared to delve a bit deeper into how the human body works. The majority of the medical community here in the UK is very conservative, they don’t entertain things unless they are fully documented by research and literature and they are very afraid of being charged with medical negligence. That is understandable to a point, but the general smugness i have encountered on the issue of PFS, it’s as if they are saying unless it’s a documented illness, then it can’t exist. Which is ridiculous considering how little they know about many illnesses and the willy nilly nature they hand out certain drugs like propecia and accutane, yet they don’t think other medical problems could develop from their use.

I always describe PFS as CFS to close friends when i have to tell them something has happened to me, due to the similar nature of the symptoms. Still quite funny (but encouraging as well) to see so many much of the terminology and theory that we are discussing on this site: methylation, switching on DNA, activating genes, gene expression, crashing, detoxing (a contributing factor to why i crashed i think) symptoms like brain fog etc. Didn’t see anything about sexual symptoms improving though!

Will definately make contact with Myhill or Dr Richard A. Van Konynenburg too see if they come on board with us on this terrific journey we are on. I would settle for 75% cured the way things are going with this, if it were possible. I haven’t digested the whole the page and links yet but will do and update on any developments in the future.


#480

hey,

well, I also have to laugh, when some people with PFS tell me CFS is a dubious diagnosis. Black and white thinking.

Even here something for you guys to laugh:

I was in the Uni with my problem at the beginning. Not some doc´s outside, a Uni! Okay?
With a smart Professor. They checkt my Testostron and wrote a letter to my normal Doctor.

“with the normal Testosteronlevels doesnt expain endokrinological those symptoms”

Well, i told them i took a 5AR inhibitor. And what does that do???

These are our geat Proffessors! the smartest guys around! He´s T leves are ok so no problem.
What is about DHT??? I was shocked of those big idiots!

I wrote them a letter, to let them know how stupid and arogent hey are, never get something back. Well well