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


#361

mens rea - what does that have to do with methylation? maybe that should be posted in the chillin thread


#362

Perhaps not directly relevant but i was intent on proving my earlier point as enuciated by Dr Crisler also. Little or no response to TRT doesn’t mean androgen resistence and, indeed, even non-PFS patients exhibit this “response” to TRT.


#363

Had to share this: Mechanism Behind Demethylation Pinpointed in APC Gene Mutants
http://www.sciencedaily.com/releases/2010/09/100917183031.htm

Any thoughts?


#364

Been thinking there are still a few things that don’t add up very well to this theory:

  • prostate pain - THIS SHOULD NOT HAPPEN IF PROSTATE WAS INSENSITIVE OR HYPERSENSITIVE - it would either shrink or grow in this case
  • improvement on antibiotics
  • the complex system proposed by this theory on how some AR is hypersensitive and others are not coupled with a change in hormonal levels in some of us.
  • still lose my hair, I can put muscle on
  • antibiotics helping
  • increasing testosterone increases prostate pain.

#365

Thats because awor’s theories are ridiculous…


#366

No its a valid idea. Just unproven as of yet. Other ideas have weight and the improvements of both tryingnottoworry and solonjk are interesting too.


#367

The main shortcoming of this theory, I think, is that it does not exclude the possibility of ours being a hormonal problem*.
Reading from older posts, it seems that the only argument that “excludes” the possibility of being a hormonal problem is that “TRT works for everybody, except us”. Well, that’s simply not true. There are a lot of people who never took any drug, who had a hormonal crash similar to ours, and for whom TRT does not work. Just take a look at Crisler’s forum and get an idea. Whether TRT works or not seems not to depend on the genetic of the person, but on the value of other hormones than T.

If anybody has any convincing argument that proves that ours is NOT a hormonal problem, please open a thread and discuss it.

*Where hormones are out of whack and the system is stable in this degraded state


#368

This theory is able to be tested, and will be tested soon enough.

In fact is anybody in contact with ZJM? It would be good to get an idea about what is happening there…


#369

Awor’s theory is far from ridiculous. It’s been shown that environmental stressors can cause epigentic changes not only in the subjects studied but also in their offspring for several generations. Dropping 60-70% of your DHT over a period of time certainly sounds like a stressor to me. In a study in Holland mothers who nearly starved during one winter during WW2 (1944-1945) were shown to have children that had impaired glucose tolerance, hypercholesterolaemia, raised blood pressure and higher rates of obesity in adulthood. Your DNA may not change in the short run but your epigenetics certainly can and its seems fairly easily. The Darwinian idea of taking millions of years to change pheotype is old science. There is a program in Eruope now mapping epigenetic markers - the Human Epigenome Project. Remember, the Human Genome Project took 13 yrs and that was only 25k genes.


#370

It’s known that during androgen deprivation therapy for prostate cancer (ie, decreased DHT via 5AR inhibitors like Finasteride) can cause androgen receptor mutations, as the prostate cancer cells deprived of androgen mutate to adapt to the low androgen environment, so they can continue thriving and eventually become hormone-refractory (resistant to androgen deprivation).


Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer
jnci.oxfordjournals.org/content/93/22/1687.full

Molecular Profiles of Finasteride Effects on Prostate Carcinogenesis
cancerprevres.aacrjournals.org/content/2/6/518.short

Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: Implications for chemoprevention of prostate cancer.
ncbi.nlm.nih.gov/pubmed/21557276

The antiandrogenic effect of finasteride against a mutant androgen receptor.
ncbi.nlm.nih.gov/pubmed/21386657

Androgen Receptor Gene Alterations and Chromosomal Gains and Losses in Prostate Carcinomas Appearing During Finasteride Treatment for Benign Prostatic Hyperplasia1
clincancerres.aacrjournals.org/content/5/11/3578.short

Mutation of the androgen receptor causes oncogenic transformation of the prostate
pnas.org/content/102/4/1151.full


#371

So, this means that the receptors are capable of performing their function even if the level of androgens is low. Isn’t it exactly the opposite of the point you are trying to make? If that was our case, we would be fine even with a low level of androgens because our receptors can adapt to it, or not? (Not asking this sarcastically)


#372

No, its not opposite his point. Genes “adapt” by either overexpression or underexpression. In the case of hormone refractory prostate cancer cells the AR gene is overexpressed. cancerres.aacrjournals.org/content/61/9/3550.full.

As you know, the theory is that ours has been down regulated to varying degrees per case and signaling is underexpressed.


#373

I’d like to throw out another theory. Dose response is often an inverted U - optimum in the middle, and worse at high and low dose.

The higher you upregulate the gain in part of your system, the smaller the window of input that will keep you at the top of the inverted U. If you upregulate high enough, making the gain in your system response to changes in dosage too high, you’ll be unable to control your system precisely enough to hit the optimum, and will instead thrash back and forth between the too little and too much input.

That sounds a lot like the experience of finasteride cessation that I hear. While you’re on it, cells are starved for DHT, and the gain gets turned up. When you stop, and that increase gain is hit by a physiological level of DHT, the response is huge, and your system thinks it is being flooded with DHT, and so invokes a feedback mechanism to put a stop to it. So on one end, you’ve got a huge gain, and on another, a huge negative feedback, and you’ve now get a very unstable system that always overcorrects out of the optimal range.

I know that’s a little hand wavy, but I think the principle is basically correct. You want to tune back the gain everywhere in the system so that the system becomes controllable again, and the window for hitting the optimal inputs gets large enough to actually hit.

It’s not just what the absolute level of the hormones are at. The levels for all the gains in the system matter too.


#374

Hmm - should we be found to have decreased AR expression, there are scholarly articles indicating that AR expression can be increased w/o using specific demethylating agents.

Endocrinology (1990) 126 1165. In fibroblasts cultured from human genital skin which contained very low amounts of 5-alpha reductase, 2 nanomolar tritium-labeled testosterone [which is sufficient to saturate ARs] produced a 34% increase in androgen receptors as measured by specific AR binding, the best assay method known, and 20 nanomolar tritium-labeled testosterone produced an increase of 64% in number of ARs.

Note: 20 nanomolar free testosterone is approximately 400 times physiological level (normal level in humans is approximately 0.05 nanomolar)

This is an excerpt from the following article on androgen receptor regulation: mesomorphosis.com/articles/pharmacology/androgen-receptor-regulation.htm


#375

could you please give any example of such people?
you mentioned musclechatroom.com. the people on there are who got trouble after using some kind of 5 ARI in the past.

user THX consumed Betas-itosterole, the active ingredient in SAw palmetto
jansz used saw palmetto for 15 years.
chemman got into trouble after using Tribulus for six months.
there are few who used some chinese herbs even some have consumed Fin.

These are few examples. I am sure if you pm them you will find some more stories behind their crash.
Another point to notice is some users got hypogonadal after porolong use of steriods they went on TRT which worked fine for them then to minise DHT they used fin or SP and got into trouble.

Human maichine is not that weak.


#376

Here are a few examples of people who

  1. have never took any drug (propecia, saw palmetto, SSRI, steroids, or the like)
  2. have hormonal issues that look like ours
  3. have tried TRT unsuccessfully

[musclechatroom.com/forum/showthread.php?17532-becoming-a-eunuch-!!!-(&p=138861](http://www.musclechatroom.com/forum/showthread.php?17532-becoming-a-eunuch-!!!-(&p=138861)
musclechatroom.com/forum/showthread.php?4489-Leanguy-s-lab-updates
musclechatroom.com/forum/showthread.php?18036-Testosterone-tolerance&p=146671#post146671
musclechatroom.com/forum/showthread.php?17730-Why-has-Testogel-caused-brain-fog-depersonalisation-etc-(PLEASE-HELP.


#377

Actually I think the first guy you linked to took sp and is on this forum.


#378

the first user used acai berry supplement few years and got into mess then he used Saw Palmetto. and now what Acai berry is go on naturalhomecures.com/acai/ailments/prostate.html. it is potent 5ARI.
So please don’t mislead yourself or other people. Before putting any post do your home work.

About LeanGuy I can not say any thing. He has done so many thing and you don’t have his past history.
I dont know about seekonk. did you send him any pm and asked about his past herbal / fin use? If not then you dont assume his TRT is not working with out any reason.

If you have not talked to them then you are not right to say that TRT is not working without any reason.In most of the cases these patients don’t know themselves why they are sick. It took me many month to discover why all of a sudden I changed.


#379

Good post SPS.

It is very true that a vast number of substances can potentially cause this problem. We are seeing it from all 5ARI’s, including SP of course, and also isotretinoin (Accutane, generics). Many Men’s formula Vitamin supplements contain Saw Palmetto. Other plant substances also inhibit 5AR, such as soy (viewtopic.php?f=6&t=5262).

The people referred to are BB’ers if I understood correctly. All of those guys are probably using a protein supplement of some sort, some of which are based on soy. I wouldn’t rule out that a high dosed soy based protein supplement could sufficiently inhibit 5AR to cause PFS like problems with a predisposed person. Let’s also not forget that antidepressants will cause the same problems to the predisposed. Zinc is also a potent inhibitor of 5AR (ncbi.nlm.nih.gov/pubmed/3207614). Furthermore, Deca Durabolin, which is often used in bodybuilding circles, is converted to NOR-DHT by 5AR. NOR-DHT is a practically inactive androgen form, contrary to DHT. So taking Deca is like taking finasteride. Some BB’lers end up getting the same problem from Deca like we have.

Can we rule out that those guys didn’t take any substance that reduces cellular or systemic androgen levels by whatever mechanism? Certainly not. SPS, if you can carry on your investigation of this and contact these guys to find out if they have taken any such substances, that would be great. I would the results highly interesting.


#380

Right. Scientific research in the area of prostate cancer has proven this over and over again. All forms of androgen ablation therapy, including Finasteride, have been proven to do cause AR hypersensitivity.

Wrong. If you can understand this point, you will begin to understand this problem. Google the term “negative autoregulation”, preferably using Google Scholar. Learn about it. AR hypersensitivity will cause an overexpression of androgen responsive gene products. These in turn will trigger negative autoregulation, typically in the form of post translational modification. The result of which is a silencing of the AR signal, because the proteins necessary for androgenic action will not have achieved the conformational state and shape required for correct activation of downstream processes. This means androgens can no longer exert their action and adding more androgens makes the problem worse, because the AR is hypersensitive in the first place. That is presumably why TRT doesn’t work for the more severely affected amongst us. That is also why orgasm and heavy physical exercise makes those guys feel worse. Finally, that is also why many of us crash after quitting fin, because once you do that, DHT returns. The return of (even near) baseline DHT levels and a now hypersensitive AR will cause significant negative auto regulation, leading to the crash many of us have experienced.