Thanks boston. The negative autoregulation information answers my question, though, it raises a few more. My primary question now would be can androgen insensitivity be caused by finasteride while taking the drug? The autoregulation mechanism appears to indicate that androgen insensitivity occurs after stopping finasteride use. If that is the case, then what is causing long-term side effects that begin while on finasteride, as opposed to after cessation? (I’m not expecting anyone to answer this, just trying to anticipate questions that could remain assuming androgen insensitivity turns out to be the case.)
During prostate cancer and when undergoing androgen deprivation therapy (loss of Testosterone/DHT), androgen receptor can mutate or AR genes can become overexpressed to allow the AR to still bind with androgen or other ligands, allowing the cancer to continue (at which point it becomes “resistant”, or “hormone refractory”).
During this process of adapting to a low androgen environment, the AR can become hypersensitive or overexpressed.
[Size=4]Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity.[/size]
ncbi.nlm.nih.gov/pubmed/20058237
[Size=4]HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer [/size]
mend.endojournals.org/content/23/12/1963.full
[Size=4]Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer 1
[/size]http://cancerres.aacrjournals.org/content/61/9/3550.short
[Size=4]Increased Expression of Androgen Receptor Sensitizes Prostate Cancer Cells to Low Levels of Androgens[/size]
cancerres.aacrjournals.org/content/69/20/8141.full
Theoretically – considering taking Finasteride is a form of androgen deprivation (inhibits DHT / anti-androgenic effects), it is plausible to reason that undergoing androgen deprivation via Finasteride could lead to alterations in AR function/signalling, due to artificially inducing a low androgen environment while on the drug (which per some examples above, low androgen/androgen ablation can cause AR overexpression & hypersensitivity).
Then, after quitting Finasteride, when DHT (androgen) floods back and saturates the AR, the already hypersensitive/overexpressed & amplified AR signal gets “shut down” due to negative autoregulation processes (ie, body senses too much androgen signal, so attenuates/lowers AR signalling to protect homeostasis).
This “shut down” of AR signalling could be the concept of "“biologically something gets switched off” (as Prof. Traish puts it) that triggers the “PFS crash” within 2-3 weeks after quitting Finasteride, when DHT floods back and Testosterone/LH/FSH levels drop to hypogonadal values. Wether the negative autoregulation changes would occur at the AR gene expression level, post-translational level, due to protein-protein/co-regulator interactions or changes in mRNA etc, is unknown. There is also an aspect of the theory related to the hypothalamus’ involvement in regulating low T/LH/FSH output from that point forward.
I’m sure Awor could provide further details, but I believe that is the general gist of what he’s getting at. In meantime, everyone should read how androgens and the androgen receptor work: endotext.org/male/male3/maleframe3.htm
Thanks Mew - that helps to confirm my line of thinking. Pretty sure we all have candida.
(Seriously though, thanks for the info.)
Does everybody’s DHT come flooding back? Citation?
Does everyone experience a crash several weeks after quitting finasteride? Or do they quit finasteride because it crashed them?
I feel like these are statements that get made over and over and over without any backing. They are part of a decided-upon narrative and timeline of events but I don’t know how statistically accurate they are.
My DHT has never come back. As of last testing, it was still sub-range. Below the lowest value on the range.
Yes xhorndog, i quit fin because it crashed me. Dht “coming back” had nothing to do with my crash, probabaly a lack of was the culprit.
I agree
This “upregulation” of the genes theory is being wayyy over stretched. There may be some element of truth in it, but there are far, far too many variations of people’s PFS experiences for this model to explain any sizable portion of the PFS puzzle.
It’s all about the stressor signals that the artificial suppression of DHT (and/or going off it) that causes this in my opinion. It gets bloody complicated thereafter.
Don’t be too quick to poo poo the androgen insensitivity (AI) theory. I don’t think awor is proposing this as a mechanism for all finasteride related problems. As we all know, finasteride works on multiple pathways. However, the case appears to be that those who suffer “the crash” upon finasteride cessation may suffer from an acquired form of androgen insensitivity.
I would venture to guess that those who began to suffer sides while on fin were not at the time suffering from AI. However, once quitting propecia, the original cause of symptoms may have resolved, but AI may cause prior problems to remain or new ones to emerge.
For those who began to see symptoms while on P that have not resolved and did not experience “the crash,” other mechanisms such as neurosteroid imbalance, HPTA disregulation, etc., may have manifested during usage and continued after cessation.
Unfortunately, some people may continue to have problems due to non-AI issues in addition to AI problems.
Sorry former, i didnt see "sides while on fin, i had a crash.
Alright the previous day then woke up the next morning with heavy brainfog, zero libido, disconnection between cock and brain, and of course no chance of getting an erection, after a few days i could get an erection if manually stimulated, it would quickly dissapate if i stopped stroking it. To this date i have had no resolution.
Previous to the crash i had i was not really getting any sides.
I guess i had the “fin crash” that some guys have weeks after quitting, just while on the drug.
Well in my case i just slowly got worse over time (post-fin), no crash or anything. This is also a popular experience with guys on here.
AI can’t explain that nor would it explain various reported recoveries, some of which induced by medical and some, seemingly, natural.
Those two things are just too big to ignore, IMO. I don’t see how we can start saying some people, despite having identical symptoms in many cases, have AI and others don’t.
I’ll digress though and wait for the study results.
I’d like to keep this thread on topic pls. Let’s just wait and see what the results of the study reveal.
Mew, or anyone else for that matter… will the results of this molecular study reveal whether we are androgen insensitive or whether we have epigenetic changes?
Couldn’t we be androgen insensitive BECAUSE of epigenetic changes?
Are there any preliminary results yet?
Also am i right in thinking PFS doctors had a conference this week?
Also for those who haven’t please do participate in the genetic study. I am just filling out the forms now.
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Can you help me out, I want to do the genetic study too. Where can I get forms?
I just came back from the PFS conference in Italy and would like to briefly report on the status of the research projects:
Study of penile skin biopsies: The experiment was only completed shortly before the conference. As such, the results are still preliminary. The data is still unpublished, and I am currently not allowed to comment about it in detail. All I can say is that a significant difference was found at the androgen receptor level between the PFS patients and the control group. However, even though the difference is substantial, it seems unlikely at this point that it alone can explain the problem. In other words, it is not clear whether what we found is rather a marker for our problem or part of the root cause. In summary, even though we found something, the available data is not conclusive yet. The only two things that I believe we can say at the moment are:
- There seems to be some kind of abnormality at the AR level
- Based on the data, some form of 5AR insufficiency seems highly unlikely
We will certainly need to conduct further experiments with the available material, and possibly expand the number of cases.
The next step in scientific investigation needs to be discussed and specified now. We have already started with these talks the day after the conference, and more discussion is still required. What is clear, though, is that the next step in our investigation will require us to participate in the funding. It also may require that further specialists are brought onto the team. In any case, we are headed for a very complex investigation.
Right now, we must give the scientists some more time to conclude their work. Our next steps are to work with the scientists in order to determine how to proceed with the investigation and what it will cost. I will give you an update as soon as we have a common understanding about these two questions.
Genetic Study: The second study, which has the objective of determining genetic markers, has almost reached the minimum number of participants required. We expect to be able to send out more saliva kits to the participants in the next couple of weeks and get moving. There are no further updates here at the moment.
So the bottom line is, that further patience is required. Please abstain from speculating about this and spreading second or third hand information. I will get back to you all as soon as there is new news.
Thank Awor. Any idea on how long until you get more detailed info from the scientists?
very interesting! Thanks to awor and all the people behind the project. Look forward to seeing the detailed results and to the next step.
Also even if this is just a marker of our problem could it not help us diagnose people with our problem? This could be very useful in regards to the lawsuit.
I’ll be sending my consent form off in next few days for genetic study.
Awor i thought i read you said some come on board to test nuerosteroids. Did this happen and are there results?
Either way you are doing a fantastic job and thank you.
Yes, a first test has been done and the results caused sufficient interest to expand this into a bigger investigation within the next months. There is nothing in detail which can be communicated at this time.
Awor, is there anything you can report from the conference itself such as discussions/debates/opinions?
Thanks for your hard work.
Do these findings set us back a bit as far as being able to tie in our problem with cancer and therefore do we likley lose out on pursuing that funding?