Long interview with Prof. Roberto Melcangi from the University of Milan by Join Robb from the PFS Foundation. Prof. Melcangi says that he thinks any change to the androgen receptor (IF there is a change that is) is a secondary effect and not as important as other steroids/what they are looking at.
Would be even worse if PFS is not a on/off switch but you have to fix different things etc.
The question is whether finasteride has changed 1 main thing in a PFS victims body, which led to PFS and all symptoms, i.e. one switch led to a cascade of changes and all symptoms. In that case, a theory has to at least theoretically be able to explain what the main switch was and how that caused all symptoms in order to be useful/viable. Alternatively however it could be that finasteride changed different UNRELATED things in a PFS victims body, in which case explaining one group of symptoms (libido, ED, mental etc) while not being able to explain other pyhsical symptoms would be fine. In a certain sense, the “single cause/switch” theory is more optimistic, since reversing a bunch of unrelated changes seems almost impossible.
Since some patients only have one group of symptoms (eg only mental or only sexual or only physical) while other have all symptoms in all categories, it seems to be at least theoretically possible, that its not one singular switch but unrelated causes/switches that finasteride doctored with. I.e. one switch for the sexual one and another for the physical ones etc. Some patients are unlucky, since finasteride in their body was able to change all switches, while in others it was able to change only one switch.
In the interview, it was unclear, whether his theory is able to at least theoretically explain the entire symptom profile or not, since he said that a possible androgen receptor change could be a secondary effect caused by what he is looking at. At the same time he said he has to focus on one thing because its his area of expertise (which would suggest the theory is not able to explain the physical sides as a secondary effect or at all).
What I would like to know from him is A) Is it at least theoretically possible, that his theory/ proposed causation chain re the symptoms he is looking at can explain all other symptoms (as secondary effects). B) Does he think PFS is caused by one primary change that led to a cascade of secondary changes that led to all symptoms? C) Or does he think finasteride changed a bunch of different things that are UNRELATED to one another, i.e. reversing one change wouldnt effect the other change/symptom, since they are unrelated (except being caused by finasteride).
The only interesting thing I caught was Melcangi’s statement directly contradicting the Foundations statement that ppar a could serve as a biomarker for pfs…When asked there he says they did not claim that but statements were made???
And also the androgen receptor talk which its already been proven to have been changed, overexpressed in pfs patients so he’s wrong there if he is saying different and about it being secondary doesn’t make much sense to me but seems to be on an entirely different page from the pfs networks area of research…
Sadly the interviewer didnt really drill down on what Prof Melcangi theory is and what symptoms it can explain.
To me there are two possiblities.
Finasterde flipped one main switch in the body, which caused a cascade of secondary changes throughout the body, which explains all symptoms. I.e. all changes are secondary effects of the main switch being flipped by finasteride. Maybe for some the cascade stopped mid way and wasnt able to keep pushing over every domino, which would explain different symptom profiles.
In a certain sense thats the optimistic scenario, since in that case all you need to do is revert back that main change and then everything else will resolve
Finasteride flipped a bunch of different switches in the body, that are UNRELATED to one another (i.e. except being flipped by finasteride). In that case flipping back one switch to the PRE-PFS position wouldnt have an effect on the other switches (they would remain in the PFS position). This version of unrelated switches also seems at least theoretically possible, since some people only have mental symptoms or only sexual or only phyiscl. ones, while other have a combination of 2 or even 3 categories.
If it version 2) of unrelated switches, then the critique against the PROF. that he isnt trying to explain all symptoms (although he alluded to the androgen receptor possibly being a secondary effect), would be unfair, since flipping back one switch is useful and since the switches are unrelated.
If its version 1) of one central switch, then he might either stumble across something that might be downstream but interesting anyway or he might stumble across the main switch by accident, even if he isnt trying to explain all symptoms.
Anyways… 
No clue, just saying.
Like many of you, I’ve spent countless hours trying to understand the mechanism behind PFS, reading through the “one main switch” vs. “multiple unrelated switches” debate. I wanted to propose a unified hypothesis that tries to bridge these two ideas and explain how so many different symptoms can arise from a single drug. I call it the Dual-Cascade Model.
The starting point is obvious: we took Finasteride, which inhibits the 5AR enzyme. But this enzyme isn’t in just one place. My guess is that its inhibition delivers two distinct, primary blows to the body at the same time, creating two parallel problem-cascades.
The first blow is to the Central Nervous System. 5AR in the brain is essential for creating powerful neurosteroids, most importantly allopregnanolone. Finasteride’s primary action here is to crash allopregnanolone levels. Without this critical neurosteroid, the brain’s primary calming system, the GABA_A receptors, becomes dysfunctional. This single event is enough to trigger a devastating cascade of neurological symptoms: severe anxiety, deep depression, anhedonia, crippling insomnia, and cognitive “brain fog.” This intense neurological stress then dysregulates the HPA (stress) axis, creating a vicious feedback loop.
The second blow is to the rest of the body. In peripheral tissues like the genitals, muscles, skin, and nerves, 5AR is responsible for converting Testosterone into Dihydrotestosterone (DHT), our most potent androgen. Finasteride’s impact here is the elimination of DHT from these tissues. As a result, tissues that depend on this strong androgen signal for their health, structure, and function begin to fail. This could involve the androgen receptors themselves becoming desensitized or altered, initiating a cascade that explains the physical and sexual symptoms: erectile dysfunction, loss of libido, penile tissue changes, muscle wasting, and dry skin.
This brings us to the most important question: why do these cascades continue after we stop the drug? The hypothesis proposes that in susceptible individuals, the sudden and dramatic hormonal shock from these “two hits” triggers a lasting epigenetic modification. The body’s systems are thrown into such chaos that they don’t just bounce back; they create a new, dysfunctional “memory.” This “epigenetic lock,” perhaps affecting the genes for 5AR or the Androgen Receptor, makes the dysfunction self-perpetuating. The body is now stuck in a low-neurosteroid, low-androgen-signaling state, even with the drug long gone.
This model logically explains the varied symptom profiles we see. A person suffering from mostly mental symptoms may have a genetic predisposition that makes their nervous system particularly vulnerable to the central neurosteroid hit, while their peripheral system is more resilient. The opposite could be true for someone with primarily sexual symptoms, whose tissues are highly sensitive to the peripheral loss of DHT. For the majority who experience a combination of symptoms, it’s likely because both systems were hit hard simultaneously, with the balance of symptoms simply depending on their unique individual physiology.
For those of us who develop PFS, these dysfunctions become locked in by a lasting epigenetic change, creating two parallel, self-sustaining cascades of symptoms.
I feel this model logically connects the initial cause to the full range of persistent symptoms in a way that makes sense. What do you all think?
Re your theory LifeSucksBalls, you would also need to explain why for some the symptoms only appear after stopping the drug. For some symptoms start on the drug, for some only after stopping the drug.
Its highly complex, and maybe the “one switch” theory will turn out to be too optimistic/simplistic in hindsight. The drug obviously interacts with multiple systems that might operate independently of one another.
Again, thats a worse theory for us, since its more difficult or maybe impossible to bring back the system to something healthy, if you have to doctor with multiple things.
Lastly, there is the problem that potentially over time, the body degenerates, since its unable to regenerate/self heal etc its structures, so they literally permanently get damaged or waste away. I.e. potentially long term sufferers cant be cured.
Again, very hard to say, but those are my 2 cents.
The main switch as u say or driver would be the androgen receptor overexpressing as it does in castration resistant prostate cancer…Causing the toxicity and all the other dysregulations…but according to Melcangi no…And again he’s saying the ppar a biomarker was just something the foundation 
claimed???
This was just a mumble salad I couldn’t really understand a lot of what he said…The presenter had some good questions lined up but he had no answers…
If its the androgen receptor, why the wildly different symptom profiles of patients? How come some have physical changes and others just mental or just sexual.
I think the interview was a bit unstructured. The first question you have to ask is: What is your current theory on how PFS is caused by finasteride? Please explain step by step (from intake to symptom development).
Instead the interviewer dove right into a ultra specific question on microRNAs…
And second question is: Can this theory explain all symptoms?
Etc. I feel like the interviewer didnt ask enough follow up questions and also was a bit too eager agree with the Prof., which is understandable but basically meant that the interview was not as enlightening as could have been possible.
Because its tissue specific…epigenetic…might be in some tissues and not in others…
Yea he just agreed with Melcangi lol…yea that makes sense! Everytime he said that I was like…no it doesn’t 
I mean I applaud that he made the effort.
But you cant start off the interview by diving right into ultra specifics like microRNAs.
You start off the interview by getting a birds eye view on what his theory is how finasteride caused PFS. Let him explain it step by step from intake to symptom development first. Dont go right into specifics, otherwise the viewer has zero clue what his working theory is.
Awor was leaps and bounds ahead of them all…him and axolotl put us on this path and truly had a feeling and overview for this disease…Melcangi is reverse engineering basically with rats…I’m sure a lot of those symptoms are apart of pfs…But we need more…A real working animal model of the disease…We can only hope the current team in Europe can keep digging in for a deep understanding so we can get that disease model…We want vindicated
Lets see. There is no smoking gun yet, re androgen receptor functioning. Studies were too small / unclear to conclusively say what the hell i going on. It sounds logical and intuitive, however that doesnt mean its true. Not reacting to hormones, hypogondal like symptoms despite normal or even above average T-levels? Must be the receptor. Maybe, but maybe not.
Did awor say how you possibly treat 1000s of localized tissue specific epigenetic changes? Because that almost seems like version 2., i.e. Finasteride flipped a bunch of different switches. Unless you have a medication that induces the body to flip everything back, how on earth do you even treat something like that…
No…sickle cell treatment with crisper…That’s ONE gene lol…And remember Melcangi calls it FW…Finasteride Withdrawal…So he had 3 groups of rats for this study as someone asked about here earlier…What he calls Finasteride Withdrawal, is it really PFS like a human gets?
I’ve heard far into the future there will be nano bot tech where they inject these tiny robots into the patient and it could go across multiple tissues and cell types repairing genes but that’s star wars type stuff…How to deliver a treatment? All this is truly novel…
Until they proof that its the androgen receptor, which they havent been able to, Melcangi might be closer to the truth than awor. Just because its less intuitive, doesnt mean its the wrong path.
It’s important to have these discussions to have a place for these discussions…That’s what’s missing now…The reddit? To me its more of a jumbled up place than this ever was and its very hard to follow the threads there…Melcangi is basically working with hormones…I dont know of anything hormonal that can cause these types of symptoms to this degree…
Maybe the hypothalamus inflammation and gut could cause a lot of them but there is no way to trial allo in a human…They always just say in the future…This was basically the sameyhing he released 3 years ago and what causes that? Overexpression of the androgen receptor in those specific tissues would be my guess…
They have documented this Overexpression several different times now in several different studies over the years…That means the protein has changed and this is not something that just happens nilly willy…In penile tissues but assume its the same in others as its more difficult to take samples from other’s such as the brain…
We’re basically going in circles till more researched goes deeper and we need more knowledgeable people here like in the old days having these discussions…Remember ar overexpression is not even understood in the context of castration resistant prostate cancer…
Yes reddit is terrible, since an algo chooses what pops up on the first page, which makes structured discussion impossible. It should always be the thread, where a person last posted on that pops up.
Reddit feels like an ADHD situation, just random homebrew nonsense and people jumping in and out of the community. Zero structure.
They have documented this Overexpression several different times now in several different studies over the years…
Melcangi says its an adaptation by the body to another problem, and doeesnt mean that there is a problem with the receptor, i.e. its a downstream/compensatory effect.
Yea its an adaptation of lowering androgen in the cell…
I still want the foundation to clarify this biomarker talk about ppar a?? Is it or isn’t it…One of the only bright spots I saw in Melcangi’s research…
Point being that the critique, oh he isnt focusing on physical symptoms, might be irrelevant. If physical is a downstream effect of what he is focusing on, or if physical is unrelated to mental/sexual/libido…
Lots of talk about the androgen receptor etc, but no smoking gun yet. So maybe Melcangi is on the correct path and awor wasnt.
I still want the foundation to clarify this biomarker talk about ppar a?? Is it or isn’t it…One of the only bright spots I saw in Melcangi’s research…
Melcangi cleary said it isnt, so the PFS Foundation seemingly got ahead of itself.