PROPECIAHELP: Unresolved Finasteride Propecia Proscar side effects info & discussion forum

Hi Awor,

I'd be interested to hear any updates on how you are coming along with looking into the possibility of testing for gene expression, or is that on hold for the meantime?

Regards,

MarioBros.

I was reading over this thread with great interest.

I am interested in epigenetic gene silencing through hypermethylation of a specific gene promoter.

Epigenetic gene silencing has long been implicated in cancer and its role in other diseases is becoming much more recognised in recent years.

Abherant promoter gene silencing occurs when a methyltransferase such as Mecp2 attachs methyl groups to cgp islands on a particular gene promoter. This can happen locally - such as at the site of a tumour formation - or over the whole body as is implicated in essential hypertension.

Here is some basic reading:

http://www.dreammanifesto.com/epigeneti ... genes.html

http://clincancerres.aacrjournals.org/c ... /1219.full

and in diabetes type II:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1184044

Do a search on aberrant methylation in google and there are thousands of topics. All sorts of diseases are involved.

BUT the article that caught my attention is this one:

http://www.citeulike.org/user/guhjy/article/6201812

quote:



My interest in this area started when my doctor who diagnosed me with a condition where an epigenetic change has occured to a gene asked me whether I had taken any medications at the time that I began experiencing symptoms.

They had been able to demonstrate that other medications had hypermethylated this particular gene but I wont mention which medications they were because the work was never published in a medical journal.

However, later I remembed that I began experiencing symptoms around hte time that I began taking finestaride.

The bad news is that is not possible to normally obtain a test to assess the methylation status of particular genes. I was able to in my case and the methylation on the specific gene promoter was 100%! The gene was totally non functioning.

The good news is that there are already a number of medications that have been shown - through various mechanisms - to inhibit the transfer of methyl groups to replicated DNA - demethylating agents:

http://en.wikipedia.org/wiki/Demethylating_agent
http://en.wikipedia.org/wiki/Azacitidine

and some natural demethylators:

http://www.cancercompass.com/message-bo ... mid=303055

Very interesting, but pretty far over my head. You said:



Did the gene you were testing for have anything to do with finasteride? If not do you know of a gene that can be tested for finasteride effects?

though all this epigenetic stuff might be interesting and the reason for everything etc...., we will not gain information in this regard AT ALL!
Why?
1) we don't have a microarray study done, especially not a methylation specific one!
2) we don't have a control group for a potential microarray study, we don't even have a well controlled study group in this sense.
3) Consider this for a second - even though in the last decades millions of dollars were spent on cancer research including all kind of sophisticated techniques there is no cure available from any drug company.
4) Why don't we consider all aspects of the genome and start talking about non-coding RNAs etc... .??!

I am willing to spent my last cent to get out of the shit, but this is a dead end road here.
We need to take action in things we can do now!
Go and measure 3adiolG levels....., perform urine tests etc...whatever...

awor, i've read through the post and i think i understand it except for one thing. are altered gene expression and androgen insensitivity necessarily mutually inclusive? I understand that a micro-array test is required to test for gene expression but as i understand it androgen insensitivity can be tested by means of a test to examine the response of SHBG to stanozolol.

http://www.springerlink.com/content/5xke760vmwl9xf47/

"The SHBG test provides functional information about the severity of the receptor defect in vivo and hence adds to the structural information provided by DNA analysis. It detects receptor defects due to mutations within the entire gene, including the DNA-binding domain, and is a rapid, simple, and cost effective procedure."

Could you comment on whether this would be a useful test in our case, and if not why not?


ramakantesh, could you perhaps elaborate on your post a little bit?



If it is not normally available why were you able to obtain the test? i mean what was special about your case that you received "special treatment". I understand if it is a personal condition you don't want to talk about but just trying to get some understanding, that's all.



Are any of these a treatment that you are undertaking for your current condition?

Methylation is only one of many gene silencing mechanisms. We could also be dealing with some form of pathway remodeling, protein-protein interaction or just about ANYTHING - we currently simply have NO CLUE. There simply is no way we can even begin to figure out the underlying mechanism ourselves. We can't solve this with google, we need a whole team of scientists. Our problem is absolutely cutting edge, bleeding edge, beyond-the-edge science. The things we are talking about in this thread didn't even appear in the studies our doctors did 20+ years ago. That's why none of them have a frickin idea what our problem might be. Not even guys like Crisler who have seen dozens of us seem to get it.



The article that you are referring to is talking about genetic mutations of the androgen receptor. This is hereditary and has nothing to do with our condition. If you have this problem you are born that way and typically leads to some form of androgen insensitivity syndrome (AIS). I am talking about something completely different: We don't gave a genetic defect but rather our receptors are not reacting to androgens the way they're supposed to. This could be due to some epigenetic change. This is a very hi-level statement which has since been suspected to be the cause of many other related problems like PSSD or what Accutane sufferers are experiencing.

See: http://www.propeciahelp.com/forum/viewt ... 9268#19268

Let me turn this into an analogy, which is a little easier to understand if you're not into this whole science stuff:

Imagine an electrical socket in your home doesn't work. The socket was installed correctly when they built the house and used to function perfectly. All of the sudden, you can plug in whatever you want and nothing works. The reason for this is because perhaps the wiring somewhere in the house got damaged. Or the fuse blew.

The socket = receptor in molecular terms
The wire = signaling path in molecular terms
The fuse = one method of gene silencing, or one way to interrupt the power

Being born with a muted androgen receptor is the electrical equivalent to having the wrong type of sockets installed throughout your house. Because they put five pronged sockets all over the place, your two pronged plugs don't fit anywhere and the whole thing doesn't work and it never did.

Awor,

Have you read this post regarding androgen insensitivity? This could explain why individuals like DUSTIN on this board feel better after taking high levels of testosterone.

Study done on individuals taking 250 mg of test. 1x a week. 3.5 year treatment, patient recovered from libidio and erectile dysfunction.

LINK:

http://www.propeciahelp.com/forum/viewtopic.php?t=1417

Like the paper quoted by mariobros, this paper is also related to AIS. As I said above, our problem for sure has nothing to do with AIS - even though the term "androgen insensitivity" may seem to be good description of our problem. Again, in electrical terms (it's really a neat way to look at things): AIS always implies that something is genetically wrong with the "shape/configuration" of the "socket" (receptor). This paper is talking about a case of a guy that has an almost normal socket (doesn't have five prongs for example). Now the analogy gets a little more difficult: Receptors, unlike wall sockets, have the capability of changing their form slightly to recognize a ligand (hormone) which doesn't quite "fit". So what that paper is basically saying is that the socket moved its holes apart a little to be able to interface with a plug that it finds "attractive". That is the point mutation they are talking about.

Both chams and I have been through functional AR receptor testing to verify that our ligand (DHT = "plug") fits into the receptor ("socket") correctly. It has also been verified that the plug stays "put" once plugged in and doesn't jump out again ahead of time (receptor off-rate or dissociation rate). Both tests were 100% normal. That is why I am saying that the problem lies further down the line (perhaps somewhere in the "wiring" = gene expression). In other words, there is no point in googling the terms "androgen insensitivity" because these will invariably lead to papers which are talking about some form of AIS. Not a single paper has been written yet on our form of "androgen insensitivity" because practically nobody knows that this problem exists. Even if they did, finding out what's wrong in the "wiring" is cutting edge molecular science. Functional receptor testing is like play school in comparison.

Now to get to your question about why some men seem to react better to TRT/androgens than others - the answer to this is likely to be very simple: We are obviously not all affected to the same degree. For example: some of us have complete and total ED while others can still have sex. Some have serious, life threatening depression while others are maybe only a little "down". Some have massive muscle wasting while others can even gain. Even though we all share a common basic problem, we are still not all the same. That is why guys which are not real badly affected probably have sufficient remaining "sensitivity" to benefit from TRT. But even those should not overdo it because our basic problem is that our bodies have developed some kind of "aversion" (active resistance) against androgens. Depending on the case, this resistance may be more or less active. You can easily find out which category you belong to by just giving this stuff a QUICK (low dose) "shot" (sorry about the pun). If you don't notice any difference after a week or even feel worse, you're not going to benefit. If it feels good, you can consider to carefully continue. But if you are going in with massive high dosed DHT, then that's asking for trouble. Let's watch and see what happens to JN.

Ok, it makes a lot more sense now, the plug-socket wiring analogy is a good one.

Btw, tamoxifen resistance is another good example of receptor conformational change, meaning the receptor adapts to recognize a ligand which doesn't quite fit.

Tamoxifen (Nolvadex) used to be widely used in breast cancer settings. After a certain time (1-5 years), the patients invariably become resistant. Even worse, the estrogen receptors adapt after while and start to "think" tamoxifen is an estrogen, making the breast cancer worse.

I experienced this myself. I was on tamoxifen for about 2 years. In the beginning, the stuff used to work great against my painful gyno. After a while, the benefit started to fade and eventually the pain even got worse. It took me a long time to realize what was going on. When I came across this information, I immediately quit Nolvadex and all of the sudden felt much better.

It was a very good anaolgy awor, no doubt. Going along this line of thought, how would SARMS fit into the mix (and their subsequent anaology as compared to the ones you've just given?) Would a SARM be like an adapter for the electrical outlet?

I don't see a straightforward electrical analogy for SARMs without getting into complicated electronic engineering stuff like rectifiers and the like.

However, there probably is a straightforward analogy to explain how a SARM works that we can all easily relate to: finasteride.

SARM's do their magic by having very similar chemical properties like testosterone, with one or two important exceptions: most importantly, SARMs don't get readily converted to DHT by 5AR. It is unclear to me if they partially inhibit 5AR or just don't get processed by 5AR because of their chemical properties (and I don't think anybody really knows). Whatever, for guys in our position SARMs are a VERY BAD IDEA. As we have painfully found out, our bodies don't like 5AR to be messed with or T/DHT ratios to get skewed.

This says it all:

http://www.ncbi.nlm.nih.gov/pubmed/1733 ... dinalpos=3

Dalton works for GTX inc. and GTX is a drug exploration company controlled by Merck. Merck is one of the most prominent players in the SARM field and is well known for its particularly safe pharmaceutical products.

No thanks, is my answer to SARMs.

That's just the thing. They don't interfere with 5aR at all. From what I've researched they "modulate" the adrogen receptor, activating it without giving way to all of the negative side effects of TRT and/or steriods. There's no Aromatization whatsoever. Basically, they make your adrogen receptors more sensitive to androgens. People run SARMS cycles on their own without stacking anything else and they see rapid improvements in all male related areas......

Plenty of info just by googling "Sarms-4"

To my knowledge all SARMs have yet to pass clinical trials. I am not talking about some white powder which a guy and his dog fills into little blue bottles. If you are referring to some bb junk that you saw on a bb site, we're not talking about the same thing. Pharma is currently investing billions of dollars in SARM development. That's not the kind of technology which is available to a bb garage lab.

If you are referring to S-4 (Andarine) that GTx is developing, that stuff has only reached phase II trials as far as I know. If you know of anything else, please post (only serious sources such as pubmed please).

Well, this shit ain't no white powder, and as far as everyone using it, they are having very positive results. What the dog is doing, I don't know, but I'm sure he's not allowed in the lab that this stuff comes from.

Here's one users on going experience:
http://www.elitefitness.com/forum/anabo ... 81165.html

Here's where you can buy it:

http://www.sarmssearch.com/

Checked it out. On the sarmssearch site is says: Not for human consumption. That is probably what the dog is all about
Give me a break man. Would you seriously swallow that stuff?

LOL. That's what ALL AAS sites say. How else to you think they get away with selling steriods? "Hey everybody, come buy steriods here." lol. That source is where all of the BB sites are purchasing, and using from. You really think it's for "research" purposes? Give ME a break.....

Awor, i was looking at the article you posted, isn't this just talking about how SARMs and 5 alpha reductase are "related" in that they are both tissue specific?

From what i got from the article, the poster was saying that examining the behavior of 5 alpha reductase could help in the development of SARMs.

My understanding of SARMs was similar to that of cdnuts.

No, it's implying exactly what I posted above. Look at it that way: There is only one kind of androgen receptor. The androgen receptors in the brain, the prostate, the muscle etc are exactly the same. In contrast, estrogen receptors come in two flavors: alpha and beta.

As we know, the body needs different levels of androgens in different parts of the body. Let's forget about SARMs for a moment and just consider how our body naturally deals with this requirement: It's got a second androgen hormone, which is more potent than testosterone, called DHT (I know we all know this ). Contrary to testosterone, which is a so called "circulating hormone", DHT is produced locally where it is needed and thus is also called a "intra-cellular" hormone. This is a very clever mechanism nature has created which allows for tissue specific androgen levels (and thus gene expression at the cell level). So if we want a androgen / testosterone analog (SARM in our case) to become "tissue selective", this can only be achieved by somehow influencing something which is tissue specific and in the immediate pathway. This means mainly 5AR and possibly 3alpha-HSD.

I've been lurking BB forums keeping tabs on this drug along with users experiences with it. In all of the studies I've read and accounts of people using it, never have I heard it explained like you are trying to here. I think you may have the wrong idea about this compound. It has an affinity for muscle tissue, but barely anything noticlable in the brain, prostate and genitals, possibly because it's NOT aromatised. Hence Body Builders don't "feel" juiced in their heads, but when they go to lift, the stamina and stregnth are there. It is compared to being on cycle without feeling on cycle. 5AR isn't part of the equation here....