Terrible news then as that might have actually led to a diagnostic marker/code to recognize the condition in a Healthcare setting…Whether its the complete picture of pfs or not it might have helped suffers with things like disability payments or just not looking like an idiot to Dr’s who don’t care or believe then…
Bit early to talk about biomarker if you dont even have a clearly defined disease mechanism yet.
PFS Foundation probably got ahead of itself.
even finding a biomarker is probably gonna take decades by the sound of it, let alone treatments…
even finding a biomarker is probably gonna take decades by the sound of it, let alone treatments…
Melcangi focus on the brain and gut rings true, since I have head pressure on the right side of my brain plus stomach pains since the onset of PFS. Also I have anxiety. Something definitely going on in the brain gut axis, like he says.
But how realistic is it, that a disease as complex as PFS can be cured with current tech…Seems like a syndrome, that needs 22nd century tech to cure lol.
Melcangi specialises in neurosteroids and so will work backwards from neurosteroid abnormalities to create his hypothesis. Unfortunately for his hypothesis they found varying levels of neurosteroid levels and differences in SRD5A2 methylation status from patient to patient without different symptoms. As a result to fit his hypothesis he needed to say there are differences between PFS and PSSD, alongside different types of PFS. It seems to be fitting everything in around his neurosteroid hypothesis.
PFS Network doesn’t have the same issue. The PFSN paper AWOR / AXO did explains the hypothesis well and the differences between patient to patient is explained by the hypothesis, alongside the tissue specific differences.
AR overexpression in CRPC which is the same realm of science and logic as the PFSN hypothesis can be brought on by inflammatory cytokines within the tissues, however this is brought on by anti-androgens and removal probably caused inflammatory cytokines to increase within tissues as androgens increased rapidly unnaturally against the dense AR protein tissues. But it’s just one factor out of many that cause AR overexpression in mCRPC from anti-androgens. The Melcangi hypothesis appears to jump too far astray from the logic around inflammation + AR expression founded in CRPC research and requires strong assumptions for it to work.
RD is gifted at documentary making, but could have been more intellectual and critical whilst still coming across as nice.
The recent Melcangi paper using a rat PFS model where a handful of rats were given Finasteride for a few weeks before Finasteride was discontinued. If we got a handful of humans and did the same trial nobody would be happy with them saying this handful of humans have PFS. It’s highly unlikely even one person would get PFS.
They also knew before the paper that AlloP reduces inflammation and that Finasteride would increase it. It’s strong confirmation bias. They didn’t achieve anything in the paper apart from some fake eye candy for PFS patients. If anything if we assume all people who take Finasteride get inflammation increase then it points away from this being the singular most important factor for the minority who get PFS.
Melagni hypothesis doesn’t seem to fit my experiences including with androgens and estrogenm. It doesn’t explain why my penile tissue rapidly changed every few hours for months after my crash - it would be short thick, long thin, micro and rubbery, hourglass shaped, twisted etc… it doesn’t explain how androgens react paradoxically, how during a recovery period I had in 2015 how I had ultra supra normal functioning including double the size penis as pre-PFS, extreme sensitivity etc, it doesn’t explain the symptoms as well as PFSN hypothesis.
Since we have AR overexpression we also know that androgens in AR overexpression react paradoxically. The tissues act like they have anti-androgens when androgen + AR overexpression are combined.
AR regulation is self regulated in the tissues by various proteins including LSD1 which act as co-repressors and co-enhancers depending on the role of protein and context. We have proteins that act as readers eg. BET proteins which influence whether AR gene is on or off.
What causes the stuck state? With no specific epigenetic proof (which we will get when the next PFSN data from Kiel / Tempera university is released). It’s completely worth speculation as to whether AR overexpression is maintaining AR overexpression because tissues react so paradoxically to androgens in this state (this is a proven tissue response in CRPC) and so why would we assume the regulation isn’t paradoxical.
If anyone fancies some relevant reading to do to see into the mind of the chosen scientist for AWOR / AXO hypothesis then look up Dr Alfonso’s paper from 2017 around BRD proteins. It is about how AR overexpression can be BRD dependent (these are readers of acetylated histones and regulate super enhancers which are large clusters of enhancers that regulate many genes expression). BRD4 is likely one key player.
I won’t go into it today as it would take a little bit more time, but I will create a new post at some point on the approach I will be trialing, which involves using LSD1 inhibitor drug called ORY-2001 and specific BET inhibitor drug ABBV-744 which targets BRD proteins. I will formulate these research drugs using SMEDDS to in theory allow oral bioavailability and will take these research drugs after some hormonal suppression (dislodging BRD4 is more effective with lower androgens + LSD1 acts as a co-repressor with high androgens so it could be counter productive to inhibit it in that state but as co-enhancers with low androgens). That’s in a nutshell which would make sense if you read into BRD dependent AR overexpression, BET inhibitors and LSD1 inhibitors impact on AR expression.
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exactly. finding a biomarker might take 20+ years, and once found i personally highly doubt a cure will be possible in out lifetime. Maybe some treatment that will lessen the effects of pfs but a complete reversal seems borderline fantasy
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Can awors theory explain the fact that many people develop symptoms while on the drug? Or is it dependant on the postulation that symptoms only appear after quitting the drug?
Great info tyr…As before…Melcangi is trying to simplify the condition…I noticed he also attributed muscle wastage to metabolic disturbance but we know the over expression of ar in muscle will cause these changes etc…
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Finding a biomarker could be sig. faster than 20 years but the cure is another story completely.
Its my understanding after 10 years of just being here that pfs is caused by a combination of your specific genes…Ir gene clusters…So as years before here it was said the only way to determine this was to genetically engineer a mouse to be predisposed to develop pfs and then administer finasteride and withdraw…So…its the combo of genes that determines your pfs state as to what symptoms you get and to what degree…That has been the basis of understanding since awor…So maybe some of these rats accidentally developed the condition but how would you know? And how would you be sure as the condition has to persist for many months/years after withdrawal of finasteride and that is not what is done with these rats???
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Yesterday I looked at Altos Labs, a cell rejuvination/anti aging lab backed by bezos and others, that raised 3 billion in 2022. I felt that PFS is very similar to sped up aging (of course just another “stupid” theory), literally everything stops working in extreme cases and many sufferers are telling us that they feel like an old man. Possibly lots of bad/non functional epigenetic change happened quickly (like biological slop/littering), i.e. very similar to aging. Producing everything associated with old age: Slower metabolism, anxiety, bad concentration, no libido, fatique, collagen and bone loss in the face etc etc. Would be very interesting to see if long term PFS sufferers live sig. shorter than expected lives. But probably wont be studied, since nobody is tracking this. Also possibly PFS induced a permanent state, where the body is not able to rejuvinate and maintain bodily structures efficiently anymore, similar to the state of an old person, speeding up aging further and resulting in the deterioration of pathways/functions/nerves etc over time.
It could be that a real cure would need to come close to curing aging itself, a complete reversal of unnecessary epigentic “slop” /garbage induced by finasteride. Of course it could also be that its purely an adaptation to hormonal tinckering gone wrong, and that its easier to reverse than aging itself, if the body gets a kick from the outside, to induce it to recognize that it made a maladaption. How on earth would you however get the body to make the right change? How would you know what changes are needed? How would you safeguard against wrong changes being made? I.e. it kind of sounds a bit optimistic, more likely are thousands of changes that are hard to reverse. Very easy to destroy almost impossible to repair scenario. Especially if the disease destroys biological structures over time, i.e. due to the PFS state vital pathways are irreversibly damaged (then again you would literally need cell rejuvination anti aging tech to cure it).
I.e. my instinct here is that PFS is a disease so complex, it needs 22nd century technology to cure. Probably most diseases you need a form of complete cell rejuvination to truly cure, since the best we can do otherwise is to stop the disease from progressing, not reverse the done damage.
Anyways… hopefully the study in Finaland can enlighten us what genes make one suspectible to developing PFS. Just like with all these PFS studies however, 150 participants is not a lot for a genetic study. Ideally for a genetic study like that you would need 100x that amount (e.g. for studies on schizophrenia which has a sig. genetic component, they have 10s of thousands of participants). So we need some luck to find something.
The Kiel study only has 12 participants. Thats kind of study often gets dismissed, “too few participant”. I had that before with a doc when I showed him a PFS study, wouldnt even take it seriously due to the low number of participants.
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It’s me?
pardon me for my poor English.
observing from a functional point of view and judging from symptoms and known scientific knowledges, it seems to me that the violence of finasteride may attack all organs which relates to 5αRI and distort its cell’s program (epigenetically) and destroys its function permanently.
Depriving of 5α-reductase must be violent and destructive interference in the whole system and its harmony. Because 5α-redactase plays multiple fundamental roles in our body and has a great impact on the whole system through its homeostasis. So, the intervention definitely puts a vast burden on the system and harmony and brings huge distortion to its whole operation. Of course, our system has a flexibility to certain degree to keep its functions. But, there must be a limit. When the burden goes beyond the limit of endurance, the micro-structures which sustain various biological signals gets terribly deformed and loses their functions. (cf. Two-hit hypothesis) Such destructions may occur everywhere both in the brain and the body and at randum. Because our biological signaling system has a flexibility and its limitation and therefore all abnormal strong interference with biological signal can cause such destortions of fundamental structure, that is to say, various epigenetic dystortions . Overexpressed AR (more precisely, just as the AR system undergoes complex and bizarre transformation in the case of Castration Resistant Prostate Cancer, it is a epigenetically modified AR system that has lost its normal function) is the most decisive but one of such results.
If that so, there is no specific mechanism which causes pfs. Because if pfs had a core and key mechanism as the etiology of pfs, there should be a core and essential symptom which is directly brought about by the mechanism. Indeed the list of symtoms is limited and some of them are very popular, but we can not identify any symtom as such essential common symptom. Some patients never have sexual disorder, and others never experience insomnia. So, it seems to be simply damages of fundamental structure of our system. The only reason of its severity may be the fundamentality and cruciality of 5α-reductase. In this case, only the method of destruction, that is to say, depriving of 5AR is common. When we fire a shotgun at someone, no one knows in which the shot hits him.
I think, pfs is a kind of destruction: vast, indiscriminate, and epigenetical destruction of system; and the cause(=the violence of intaking and quiting finasteride) already had gone; unfortunately there is no cause longer and so we cannot cure it by removing the cause; there is only destructions as the result. Whatever the precise mechanism of pfs is (I really want to know it), apparently it is not difficult to imagine that it is impossible to repair this destructive damages by any artificial interference. it would be equivalent to put time back. the only chance (if it is possible) may be a self re-adjustment or re-regulation of our body through long time; only we can do is to encourage and not to disturb its process.
this is my image.
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I agree. There could be no rhyme or reason to it. Thousands of things could be destroyed. AR overexpression may be one of them but not the only one and also not the central switch. Its basically chaos theory in action. Thats why I think its akin to trying to cure aging. Its multicausal and parallel and self reinforcing. PFS has basically sped up processes typically seen with aging (“epigenetic drift”). Like with curing aging, you are trying to put back together a city, which has been severely damaged by a tornado/storm. Its theoretically possible but akin to turning back the clock. And imo this kind of tech will only arrive next century. I summarize this as the switch theory vs the chaos theory. The switch theory (awor), says that if you solve one central problem, the entire system will come back to health (AR overexpression). The chaos theory says that many parallel and independent but also self reinforcing parts have been randomly changed (epigentically), with no particular reason for it, other than that we were particularly vulnerable for drifting into epigentic chaos (akin to aging) via this outside “chemical attack”. Since its everywhere and random its essentially only curable by rejuvinating everything.
Chaos theory imo is what Melcangi is going with and its sig. more negative than switch theory.
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An analogy I keep coming back to is that of an ecosystem collapse. Finasteride didn’t just impact one component; it was like removing a keystone species. The initial, specific event—the epigenetic insult to the Androgen Receptor system that AWOR’s work points to—is the “switch.” That’s the extinction event. But the consequences aren’t linear. What follows is the “chaos”: the unpredictable collapse of the entire ecosystem. Predators starve, rivers get clogged with algae, invasive species take over. You can’t understand the full scope of the disaster by only studying the empty niche where the keystone species used to be. You have to study the whole broken system. This aligns with Melcangi’s work on neurosteroids, the gut, and inflammation; these are the downstream consequences of the foundational imbalance.
The problem is how to prove it. The scientifically ideal study—the one that would connect all the dots—is a logistical nightmare. You’d need to take tissue biopsies to confirm the AR dysregulation, draw cerebrospinal fluid to analyze neurosteroids and inflammation at the source, and profile the gut and blood all from the same large cohort of patients over time. Let’s be honest, this is practically a fantasy. It’s incredibly invasive, prohibitively expensive, and requires a level of institutional support that simply doesn’t exist for a controversial, unacknowledged condition. This is the great wall we’re up against, and it’s why progress is glacial and why the small, isolated studies, while important, never feel like they move the needle.
So, if that’s the reality, maybe we need to shift the goalposts. Maybe the immediate objective isn’t finding a “cure.” Maybe the most critical, immediate goal is just getting undeniable proof of the pathology. To get one properly funded study that moves the “persistent AR dysregulation” hypothesis from a compelling theory into a medically recognized, demonstrated mechanism of disease. That victory alone would change everything. It would end the gaslighting from the medical community and force the regulatory agencies and pharmaceutical companies to take this seriously.
From that foundation of proof we wouldn’t be looking for a magic bullet to reverse the entire ecosystem collapse overnight—the “22nd-century tech” sentiment is probably correct for that level of restoration. Instead, we could search for leverage points. Can we find a way to interrupt the most damaging feedback loops? Can we stabilize one part of the system to prevent further decline? It’s about damage control and symptom management based on the actual underlying pathology. It’s the difference between trying to regrow an ancient forest and simply stopping the fire from burning what’s left.
This is a grim, long-term fight. With a solid scientific foundation in maybe 10 or 20 years, no one would have to go through this with the added horror of being completely disbelieved and abandoned.
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Agreed - I think natural recovery as we’ve seen in some people in likely the only hope.
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Follow up interview with Prof. Roberto Melcangi. If he is working downstream then its of course not as potent as reverting the primary change (which could be androgen receptor related).
Natural recovery is a pipe dream for serious cases.
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Awor echoed the same sentiments back in 09…If it turns out a receptor related problem all we can do is try to give the body time and what it needs to recover naturally best it can…And support each other because the tech to intervene in such matters is not here yet basically…
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Natural recovery for many cases is not possible though. So for them its a bit annoying to keep hearing about it.
Tell me about it 
Melcangi is sounding like a nothing burger as well…