I agree with your comments.
Are you from an Spanish speaking country?
The rules say to not “attack” the person - I don’t think there’d be much of a forum anywhere if addressing someone was against the rules 
I am sorry if that was taken the wrong way, I only asked if you had posted before given your first post was headlined with “new cure protocol” which is quite unusual as a user’s first post. The warning to others I wrote is simply a matter of what we are prepared to host on our site - discussion can certainly continue about this by all means, however considering past tragedies from advice that has been presented with unwarranted certainty and no caution, it’s important users are informed of risks when people are banding about the word “cure” which can have a strong effect on people who are suffering.
I appreciate the AR has been studied primarily in the context of prostate cancer. Many concepts of androgen response can be traced back to the work of Huggins, for which he won the nobel prize in 1966, and I don’t think anybody claimed to have made the discovery of the AR as a transcription factor. It’s potential for a pathological role in PFS is a considerably different thing, and the latter was in fact demonstrably awor’s “discovery” and ongoing work. Here is an extract from his 2010 paper:
After 5ARI withdrawal and with DHT levels restored to baseline, a hypersensitive AR, probably
through amplification at the transcriptional level (68), will result in an overexpressed gene product if
not offset by downstream or other regulation mechanisms. Several studies have documented that
the androgen receptor has sophisticated mechanisms to autoregulate its own gene expression levels
through negative and positive autoregulatory feedback loops (71) (72) (73) (74) (75). A (genetic
network) feedback loop means that the receptor is regulated by its own gene product (76). These
autoregulation mechanisms assure that AR gene expression remains within precisely determined
ranges (73). If this were not the case, cancer, runaway muscle growth or blood clotting could occur,
which would eventually lead to death.
Those affected by 5ARI-WS share a number of common hypogonadal-like symptoms; however, not all
symptoms are experienced to the same degree by all affected individuals. Such variability is likely
explained through the unique genetic profile of each affected individual. To date, over 200 AR target
genes (androgen responsive genes – ARGs) have been identified (69), giving credence to the fact
there are innumerous androgen mediated processes within the body which can be affected to an
individual degree by gene regulation mechanisms. Alternative RNA splicing can further increase the
number of proteins translated from target genes (77) (78).
It is assumed that AR hypersensitivity is the result of a set of modulators that enhance AR transcription (enhancers, promoters, activators) (67). If the resulting level of expression becomes too high, another set of autoregulation mechanisms will take effect to offset this (71) (80) (81) (75) (79) (82), for example:
- modulators and chromatin remodeling at the transcriptional level
- DNA methylation at the transcriptional level (83) (84)
- RNA splicing at the posttranscriptional level (78)
- RNA sequestration at the translational level
- Posttranslational modifications such as phosphorylation, acetylation, sumoylation, etc.
The effect of these modulators or the balance thereof can be temporarily modified by epigenetic
regulation processes such as phosphorylation, or more permanently modified by processes such as
DNA methylation. Such modifications are considered to be responsible for more or less permanent
changes in gene expression levels. It has been hypothesized that epigenetic changes in gene
expression are the basis for persistent side effects from drugs. This includes permanent side effects
from 5ARI class substances such as isotretinoin (85), and presumably other 5ARIs such as finasteride,
dutasteride and even saw palmetto extract (SPE).
Within 7 days of quitting the 5ARI medication…baseline DHT levels are restored (91). Following the suppression of DHT by over 70% while on the medication (i.e. finasteride) (91), the return of baseline DHT levels represents a rapid increase of DHT concentrations at the cellular level by over 333% (from 30% to 100%, which equates to 1 / 0.3 = 3.33). Depending on where the body has determined the reference point for “normal” androgen levels to be (i.e. 30% mark or 100% mark), and assuming the body has become “accustomed” to a significantly reduced level of DHT (and thus gene expression) while on the medication, we postulate that a rapid restoration of baseline (100%) DHT levels after a period of deprivation may be perceived as excessive by the body…in effect, all dependent downstream processes (e.g. induction of 3α-HSD enzyme) become downregulated.
I believe it’s quite apparent that’s what is being somewhat rehashed here.
We have seen that further exposure the body can “react” (often after miraculous improvement) by a dramatic increase in deleteriously affected sites “tipped” into this state, and increases of symptomatic severity. What is the mechanistic reasoning supporting how this approach could help patients who demonstrably have overexpression of the AR median 5yrs after return of physiologic androgens, in some cases significantly increased T or DHT vs baseline measures, and some already secondarily hypogonadal? When talking of “sensitizing”, this is, less abstractly, meaning chromatin modification via the epigenetic processes listed above, as recently affirmed by Traish recently in his paper titled The post-finasteride syndrome: clinical manifestation of drug-induced epigenetics due to endocrine disruption. So once this takes place, even if what is suggested was pharmacologically achievable, what is the evidential basis that gradual reintroduction of ligand will undo this? While the rapid return can certainly explain the crash - it’s histone alteration that would explain the changes that lead to it, and as you seem to agree these would initially take place during the use of the drug, as does the invariable ultimate refractory response seen in ablation treatment for pca. I don’t see how there’s any mechanistic underpinning to suggest this could have a remedial outcome.
Nevertheless, if it is something you go ahead with I’ll wish you good luck. We are well connected to scientists involved in PFS research and are interested to hear you are a practitioner yourself with contacts with experience studying pca/crpc. If you believe they would be interested in conducting research into the condition please do reach out to myself or @awor via PM. 
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The only question I have is how people getting PFS/PAS from one pill… there is no withdrawal syndrome. This fact is not ‘‘explained’’ by any theories. And one pill wouldn’t alter DHT that much ?
I appreciate your explanation and you are right its always good to warning people about side effects of antiandrogens. As its my first post I was not aware about your rules and your sensitivity toward certain words. By using “cure” I only mean this can actually work. Its a possible hypothesis for a cure.
Thank you for sharing this paper. I appreciate all your efforts for helping all of us and even the idea of this forum is genius.
This theory is something I am working on it, thinking and debating with others. The reason I shared it here is just to receive your arguments and evaluate it. I am still develloping my strategy to do it.
Let me explain it in more details.
I agree with you, when the body is confronted to finasteride which by inhibiting 5 alpha reductase decreases DHT, it reacts by
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Activating HPG axis to increase testosterone.
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Epigenetic changes leading to overexpression of androgen receptors.
This changes actually is not the crash itself. In this state the homeostasis is still established. Overexpession of receptors is balanced with the lack of androgen.
My theory is that if someone continues on exact same dose without missing any doses or doing something else which can affect androgen system like taking steroids, the crash will never happen.
After discontinuation the sudden rise in DHT combined with overexpressed receptors leads to another epigenetic changes but this time not at the level of receptors genes but after that meaning androgen signaling pathway for example the genes which are the targets of androgen receptor dimer. And this results in an impaired androgen signaling. The overexpression of androgen receptors shows that the pathway is impaired and this overexpression must overcome the probleme but it can’t because the problem is after it , or the receptor proper functioning is impaired.
I think a sharp decrease in androgen signaling can reverse this epigenetic changes. The epigenetic changes are so complicated that we can’t target it and change it to a manner that we want. It can’t be controlled toward a specific goal. What I say is by creating this state the body will reverse epigenetic changes by itself. This system is designed to reach balance. When DHT increases the responsivity decreases. If we decrease the stimulus , it reacts by increasing responsivity.
The first step to a possible cure is reversing these epigenetic changes. Then we can find a way to keep the balance. Increasing gradually DHT can work. Its a theory.
I am in contact with the departement of urology and they are interessted in Post Finasteride Syndrom because if we find a cure it can work for anyone who has a low sex drive for any reason.
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Department of urology from what medical centre?
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The way I got PFS is the following. I took finasteride for 8 years with minor issues towards the end of the period. I stopped for 6 months during which I was almost normal. Then I resumed finasteride and got PFS with the first pill. I tapered for a month after that but there was no difference. That was 2.5 years ago and there has been no change in my condition since then.
So in my case DHT didn’t rise suddenly but dropped suddenly. I think there are a lot of users on the site who had the exact same experience as me, and other users who got PFS with their first pill ever. This should be taken into account when coming up with a theory of PFS.
Isn’t the reversal of an epigenetic change an epigenetic change in of itself? So if I’m correct you’re postulating that your protocol is founded upon the notion of creating another epigenetic change which ‘undoes’ the effect of the induced epigenetic change?
I assume this is predicated on the notion that people with a propensity for developing PFS have Androgen systems which are more susceptible to epigenetic changes when the system is subjected to a ‘shock’.
It also makes the assumption that the change can be reversed by inducing a ‘mirror’ state. I think this is a big assumption to make. It sounds appealing, perhaps too much so, almost like playing a video in reverse. Does the complexity of the human body where so many mechanisms are at play allow for such a neat dynamic?
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I don’t follow. Methylation is happening many millions of times a second in the body and can occur as an immediate and essentially permanent organism-level adaptive response to environmental influence (Martin, E.M. et al, 2018). This is a key reason why endocrine disruptors are becoming a focus of scientific research. “A withdrawal syndrome (also called a discontinuation syndrome) is a set of symptoms occurring in discontinuation”. As one of those people regretting one dose, there certainly was and is. It’s not a perfect title but it conveys that a majority experience of some worsening or development of symptoms after cessation, in addition to those who have lasting symptoms that onset during use.
Regarding that “one pill wouldn’t alter DHT that much”: I know people take a “common sense” approach when thinking about this but that is not helpful as the drug’s dose/response is highly unusual. It’s been demonstrated all doses lead to steady-state plasma levels of DHT between 0.1 and 0.15 ng/ml. The discontinuation of treatment results in a normalization of DHT levels within 2 weeks, irrespectively of the finasteride dose (0.04 to 100 mg). “finasteride…results in significant suppression of serum DHT at all doses tested.”. Effects of Finasteride (MK-906), a 5α-Reductase Inhibitor, on Circulating Androgens in Male Volunteers (Stoner et al 1990).
That is, remarkably, the same ballpark outcome in DHT reduction and normalization for those who, over the study period, took totals of 0.5mg and 1100mg.
Yes, I was asking for a mechanistic basis supportive of any of this - approrpiate scientific literature suggestive of applicable outcomes that would support the idea. As @orthogs suggests this is far too simplistic and I was hoping for specifics. Steroid receptor overexpression is a key element of hormone refractory cancer, and a sharp decrease in androgen signaling doesn’t reverse the chromatin remodelling - it further increases AR expression. It is referred to as “castration resistant”. If you are considering that local AR levels are contributory to the pathology in PFS (Khera et al, 2018), given we have instances of permanent additional harm and suicide from further antiandrogenic exposure, I would argue there is mechanistic support for the opposite in theory and in practice. While (very abstractly) as you say “the system is designed to reach balance” under normal conditions via a host of regulatory mechanisms, many discussed in awors work, it is no longer happening in PFS (Di Loreto, 2014). What you said in this quote is not happening in either circumstance, and there is not an external intelligence knowing where the “right” settings are for the epigenome. It is determinant of cellular instructions, responses and behaviours. I don’t think it’s credible to acknowledge the complication of the domain and assume such an outcome based on unsourced assertions.
As it’s a hunch, I’ll hop out now and wish you the best. Thank you regarding the website - we work very hard for everyone here. That’s great to hear regarding your colleagues and I hope you can encourage them to conduct primary patient research of some kind, even if it’s just histological investigation.
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You took finasteride for 8 years so the epigenetic changes related to androgen receptors have already be done. When you stopped the drug a rise in DHT has happened but your body had not reacted yet. Because of its complexity its not predictable, we dont know all the factors involving. Or maybe even then you had the crash but somehow your body compensated and you did not knew it until you resumed finasteride which by lowering DHT had revealed what it was done before.
What we know is that the problem appears to be related to changes in finasterid levels.
You are right. When I say reversing maybe its not the exact same changes that will be reversed. But something which allow the body to overcome the low androgen signaling that we have created. If the problem is theses epigenetic changes the only way to do it is by undoing them , if there is a methylation it must be demethylated. We dont know when the scientific efforts will result in an complete understandig of all theses changes effects and would be able to change them selectivley. But its a really long way and we dont have time.
If there was a study conducted on what happens when there is a rexposure to different amount of drug it would really help. But I know that when I was taking finasteride changing doses affects me in both bad and good ways. So maybe using correct doses it has the capability to reverse these changes. Another drug will induce another epigenetic changes which are not close to finasteride’s.
Now its proven that every single drug that we take can induce epigenetic changes, even if you are very stressed these changes happen like PTSD.
Uh, no dude. I did not have PFS for those 6 months. No epigenetic changes had happened. You cannot bend the facts to fit your theory.
This is true. Even if the impending Baylor Study does identify epigenetic changes in PFS victims, the next question is what can be done. Even if the changes were largely homogenous with the victims involved in the study, what could be done to treat them.
Just today I was reading about a gene therapy drug called Zolgensma for treating spinal muscular atrophy in infants (https://www.sbs.com.au/news/world-s-most-expensive-drug-costs-3-million-for-a-one-off-treatment). It took a good deal of development and over 1 Billion in research dollars to get it off the ground.
It’s remarkable that such a drug can exist, and one wonders if a similar mechanism can be used to treat/cure PFS victims. Of course such sums of money are unrealistic to get together. I assume this why the foundation, axolotl and awor are attempting to find commonality between PFS and other similar syndromes. Only then could pharmaceutical companies be seduced into developing a drug which could help victims across the range of syndromes.
This is making many assumptions, naturally. Homogeneity to me stands out as being a big issue. If every victim has a unique series of epigenetic changes, I don’t see how a drug could be customised for the individual. I suppose we just have to hope/pray for homogeneity to be the case.
“Steroid receptor overexpression is a key element of hormone refractory cancer, and a sharp decrease in androgen signaling doesn’t reverse the chromatin remodelling - it further increases AR expression.”
Exactly in prostat cancer a sharp decrease in androgen induces the overexpression of AR but the pathway is intact , the tumor continues to grow and responds to androgen It increases its responsivity. So until this stage its good for us.
The problem is not the overexpression of AR itsef. Your seems to be focused on AR overexpression. But its not a bad thing, every where in the body that a pathway is impaired the receptors are overexpressed. AR are overexpressed every time the signaling is too low. So maybe their functionning is impaired and they are everexpressed to compensating.
A sharp change in androgens can induce chromatin remodeling and epigenetic changes. I dont know why you say it doesnt.
We have not any study conducted which has monitored epigenetic changes induced by finasteride using different dosing and repeting on and off intervalls to see what happens. Every single situation is different and can induce different results. If a similar study exists I appreciate if you share it with me.
What you are waiting for, a miraculous drug which can safely reverse changes does not exist and will not until 50 years at least. Even so like finasteride their effects can t be fully understand and controlled forexample they can induce cancer by promoting oncogenes. I think our body has been impaired and we need a cure now not in 10 years.
I agree with you, it’s just a theory and a more sophisticated model needs an understanding of all factors. Forexample
when you retake finasterid it can activate HPG axis and increases testosteron and maybe testoseron or other androgens than DHT causes the crash in your case. I’m not saying that we know the exact mechanism. What we know is that changing doses is more probable to induce the crash.
What I want to know is that if changing finasteride doses can reverse the problem.
Homogeneity must exists because the underlying mechanism is commun, the variation between symptoms can be explained by different sites affected or how each person respond to theses changes.
My idea for a protocol by increasing androgen signalling
The theory seem to be close to the reality, Homologous desensitization
There is a guy that used Triptorelin and then trubulus after, and he had been for 4 year with very high libido and strong erections ( cure )
Triptorelin suppress LH, I believe that it going to put testosterone to very low level close to zero, DHT it will not be produced, androgen receptor get sensitazed and funtion again.
There is aother guy that by accident Methylprednisolone (a glucorticoid ) seem to solve his issue.
Glucorticoids treatment even a low dosage low significantly testosterone levels imagine a high dosage for 5 days,
Both cases the substrate androgens (testosteorone is suppressed to a really low level ). both reversed PFS completely.
But using adrogen to suppress LH withdraw it and use propecia again ? mmm I think that maybe there are other methods to get the same result maybe Triptorelin under profession supervision.
Hey, this is something I am very fearful of. An optimistic conjecture would be that, although each individual may have their own unique post-drug epigenetic profile related to the pathology of this condition, each particular element may be treated similarly due to their relationship.
An example would be (making an assumption that excessive androgen signalling caused epigenetic silencing of various AR target genes) upregulating a significant cluster of AR responsive genes by way of histone demethylation with a drug like clenbuterol.
Something similar might be achieved by targeting common androgen response elements with CRISPR systems modified for demethylation in a similar manner as discussed here and here.
There is a technology called TALE(N)s that has been used in much he same way as CRISPR experimentally to modify specific areas of DNA and chromatin.
I think it’s possible that increasing expression of AR targets may severely exacerbate the problem, but goes to show it is possible to do something like treat multiple targets in one fell swoop.