Here’s the thread: The first Trial with SAGE-217
1 Like
Melcangi also did a study on the 5-AR gene in CSF of PFS patients and found that 56% of the patient group had altered epigenetic methylation compared to control group of 8%. Highly significant results and it shows something impt it is only present in 1/2 of the PFS group so it begs a lot of questions. Epigenetic modification is most definitely involved in PFS but it isn’t the same for all patients so there needs to be a more unifying cause. It is notable that all patients showed impaired neurosteroid levels.
It isn’t clear what this current Melcangi study is about and there’s such a large bias here that people are rejecting the work without having relevant info and just making assumptions about it.
Nice straw man argument. Your claim is that epigenetic modifications can’t be a unifying cause simply because the modifications were heterogenous for that one gene. Claim doesn’t hold up since there are 1000s of genes. Why aren’t you looking at the study that looked at AR overexpression and found that it was present in all patients that were studied? Is that not notable for some reason? Or that Baylor’s analysis found widespread epigenetic dysregulation?
For the record, you are alarmingly lacking in self awareness.
Cool. Don’t think there are any reported cases of people having their penises disintegrate as a result of adverse neuronal changes caused by immune, mental or social stress.
that’s not what a straw man argument is. But there are many many things that can cause epigenetic changes so even if you assume that there is a universal and precise epigenetic change in all PFS patients then you need to figure out how that epigenetic change was created in the first place. Neurosteroid impairment combined with some kind of other catalyst can definitely explain that and makes a lot of sense when combined with many other circumstantial factors and evidence. they are also very clearly implicated in sexual functionality so yes, there is a very strong reason to believe that neurosteroid disturbances would be responsible for the main symptom seen in PFS (but many others too).
you’re still misunderstanding what I’m saying though. there are obviously many complexities involved in PFS or it wouldn’t have continued to be a mystery for decades. there could be an infinite number of stress factors in combination with the neurosteroid depletion that result in structural damage. there is a reason that PFS happens in a minority of patients that take PFS and obviously taking finasteride would have to be a necessary component to developing PFS. the interaction is what you are misunderstanding.
You are right - it is not a strawman argument. I have my logical fallacies mixed up because I am constantly seeing them on this forum.
No matter what way you spin it, the biggest issue with considering neurosteroid impairment as the root cause of this issue is that it does not explain how androgenic dependent issue literally disintegrates in some patients. Why consider an answer that can’t explain all the symptoms patients are experiencing, when there is an answer that does?
The jump from all of the negative effects of neurosteroid depletion to having androgen dependent tissue disintegrating is a huge one. I’d be willing to consider the possibility (and honestly inclined to, because it would make solving this problem a lot easier), but I don’t see how it’s possible to make that jump.
1 Like
I’m not sure exactly what you mean by ‘androgen dependent tissue disintegration’. But I would consider posing your question to Dr. Melcangi before assuming that the explanation does not exist.
Epigenetic modifications are a really hot new topic in biology and nearly everything will cause epigenetic modifications. Psychological stress or PtSD will cause epigenetic changes. I do think it is worth exploring PFS from every angle, obviously including epigenetic research, but I don’t think it makes sense to categorically reject neurosteroids other than competition for donations which I don’t even think is so practically relevant here. I think Melcangi’s studies will likely get funded without donations from the forum but I just don’t think it makes sense to categorically dismiss it.
Everything here is still largely in the exploratory phase and it will take a long time for the science to catch up here. I’ve been living with this for over a decade and have seen the pace at which things move so I’ve decided to focus on trying to bolster my health more holistically. I still have an interest in having the science get figured out though.
1 Like
university research initiatives get corrupted all the time.
literally happened to us
1 Like
Guys, if you want to donate to the study…donate to the study. It’s pretty simple. Nobody is stopping you.
I’m not sure what this circular discussion is achieving.
1 Like
Guys, what about the research in Kiel? What is the reason for the delay? I read about 3 researchers who can help us there - it’s a strong and young team.
Is it really hard for us to find 12 sick people in Europe?
No, I’m asking without pretension.It’s just discouraging.
There’s not really a delay as such, the process of organising a study just takes time. If we were able to use the samples collected by Baylor as originally planned, we’d be well underway by now, but given we had to find a clinician who could help us collect new samples, it’s meant the process has taken longer than we hoped.
Finding a clinician who is familiar with the disease, willing to participate, willing to be a publishing author, takes a lot of time in itself. There are very few of those, especially in Europe. Organising the logistics of how those samples will be collected at their facility takes time. Organising the logistics of how samples will be transported to the research facility, safely, and stored to avoid contamination, takes time. Writing clinical surveys in two languages and importantly, writing an ethics proposal in consultation with researchers, takes a lot of time.
We have the numbers we need for the study to go ahead and we’ve already selected the patients we think are most suitable. Now we’re just waiting for ethics approvals to go ahead before we can put wheels in motion.
Would we like for this to have happened faster? Of course. None of us want to delay research into this disease any longer. But we also needed to do things the right way, which unfortunately takes time.
7 Likes
Did you let these people know they’re selected yet or no?
I cannot help but agree with Frustrated’s comments.
I personally believe it’s totally ok for PFS Network to refrain from funding Melcangi’s studies but I believe PFS Network should also stay away from making content related judgements with regards to Melcangi’s work. He’s one of the few actual scientists who’s been consistently putting out work towards understanding this disease and thereby also raising awareness.
We’re all trying to work towards the same goal here. When PFS Network is actually expressing dismissive comments with regards to Melcangi’s work or hypothesis I wonder whether PFS Network is aware of the large power they have in influencing the PFS community.
Expressing general support and actually financially supporting Melcangi’s work are two different things. I think a community as powerful as PFS Network should, aside from financially supporting, support Melcangi’s work in every way possible. No explanation is needed since people can choose themselves who they give money to.
This is a direct example why I think PFS Network should refrain from making medically related quotes like these. These statements can be very harmful because most PFS sufferers have no medical background and will interpret these statements coming from PFS Network as true. But we actually have no clue if this example is true. Finasteride caused a disruption of hormones in the first place so dysregulated neurosteroids could very well be a driving mechanism (and actually caused epigenetic changes after).
Just like we have no clue whether epigenetic changes are a driving mechanism. We have not a single clue like Howell/Khera actually state in their Conclusion of the epigentic changes publication, quote:
Given gene expression per se is not mechanistic and does not imply causality, experiments with downstream processes of protein expression and activity should be undertaken to provide mechanistic data and clarify the results of this work.
https://sci-hub.se/10.1016/j.jsxm.2021.05.009
As you know I highly value your commitment and work for our community Mitch. I do however think it’s extremely important we are able to discuss topics/concerns like these openly and freely.
PS I have been systemically financially supporting PFS Network with a monthly donation and am also considering financially supporting Melcangi’s work.
4 Likes
is there a way the backend logistics can be prepared in advance while we wait for the approvals?
I appreciate that Professor has been consistently working to spread awareness but that does not exempt him from criticism (whether right or wrong).
we have limited resources in general, if something doesn’t seem right, id rather avoid hitting that pothole.
2 Likes
There is little point in a back and forth discussion if participants are unwilling to employ the same level of criticism towards both sides of this story, which I feel does not indicate a progressive attitude towards a better understanding of the situation and only reiterates previously established biases.
Regardless of whether you believe neurosteroid dysregulation to be a symptom or a cause, neither side of that coin justifies this study proposal. It certainly doesn’t justify the way the PFSF announcement was written and how spectacularly assumptive and over-enthusiastic it was, which I think was the main point of criticism from the PFSN, which I assume was outside of Melcangi’s control.
Regarding the study; the idea that rats being fed finasteride is in any capacity an accurate model for human beings with PFS just rattles. It doesn’t take a genius to know that. This is quite frankly a makeshift, low budget study proposal, which will be part of a legacy of countless other rats-being-fed-finasteride-studies before it.
What we need is to figure out what is going on, and then work more accurately towards a treatment suggestion from there. That’s not what this study proposal by Melcangi will be contributive to. Without an etiology or therapeutic target, and without human test subjects, none of these studies will amount to more than guesswork. Guesswork, as previously stated, is what patients have been performing on themselves albeit in a less bureaucratically correct format for the past decades and is not what we require at this point. Where I’m from we have an idiom “walking ahead of your shoes”, which I feel is what Melcangi is doing here.
So to be honest I can’t help but agree with Mitch here, and I find it a little disappointing that people seem so keen on criticizing that one sentence he wrote where maybe he should have used the word ‘could be’ instead of ‘are/is’ and it wouldn’t have been an incorrect statement (if incorrect at all).
But all that fuss in defence of what? This rat study? If you’re going to be critical to this degree then at least be consistent and apply the same level of criticism to the study proposal as well.
6 Likes
this isn’t a criticism about semantics and the foundation announcement is mostly irrelevant. the announcement was lacking in detail and the criticism here of not just the study but all of melcangi’s work was inaccurate and didn’t do anything to fill in relevant details here. nothing in the announcement mentioned a rat study, i’m not even sure where that is coming from.
my main criticism is the mischaracterization of his research and criticisms that seem to be based on assumptions and not actual knowledge or reason.
It is a rat study. Feel free to reach out to Professor Melcangi to confirm.
Even if we ignored the other weaknesses of this study, that alone immediately disqualifies this from being something worth doing.
Rats that are fed finasteride != PFS
Any insights that are drawn from observing these rats cannot be considered applicable to PFS, since these rats are not experiencing the same condition. There is no way of saying they are experiencing the same condition, since we do not know what the condition is.
Diseases are studied, characterized and understood based on looking at subjects with that disease. This is not the same. I don’t know how defenders of this proposal don’t see how important this distinction is. It’s a farce, and you are choosing to be willfully ignorant in the name of pragmatism, or fear of the long path we have ahead of us. There are no shortcuts out of this.
There is no mischaracterization of this proposal. Rats being fed Finasteride != PFS is the bottom line.
3 Likes
this is foolish and completely dogmatic, a huge problem on the forum here as I have pointed out. Science uses animal studies all the time to derive insights on how things work in humans. there are limitations to doing that but it is really arrogant to say ‘that alone immediately disqualifies this from being something worth doing’. we’re still at the point in scientific knowledge where very little is known about both neurosteroids and epigenetics but it is pretty clear that both are dysregulated to some degree in PFS patients. we’re unfortunately still at a point where basic research is needed to understand the effects of finasteride. we have epidemiological evidence and biological evidence showing that PFS is real but more basic research is needed to understand the causal mechanisms.
it is fair if you want to state your OPINION that you don’t feel its worth it to donate to a rat study, but it will most definitely render useful information. I understand that there is a strong desire to get to an understanding and treatment for PFS as quickly as we can, but rushing ahead on one track without looking at the entire picture will be likely to render disappointments and setbacks.
Even if we pinpoint a specific area or areas of the epigenome that are messed up in PFS patients, there still are not specific treatments to target epigenetic problems at this point and it would provide useful biomarkers but not much insight into the causa mechanisms for how finasteride led to epigenetic changes in a small subset of users.
I’ve been dealing with much of this stuff for over a decade so I have some rich perspective on what is realistic to expect and there is a lot of wishful thinking going on in totally dismissing neurosteroids as an important area of research.
Feel feel to criticize the study announcement as much as you want, it was vague and hyperbolic, but it is very irrelevant to the point that neurosteroid research will also be very valuable. Everybody is free to donate to whatever they want but i think it is very problematic to trash a very important avenue of research and a researcher who has already contributed a lot to the community and is interested in continuing to do so. Fair criticism is constructive and helpful but my opinion is that the official position of this forum amounts to the effect of unfairly poisoning the well which harms the entire community.
3 Likes
a real meritocracy of ideas will be most beneficial to the community at large and will have the greatest likelihood of getting us to answers and effective treatments the quickest
all research proposals have strengths and weaknesses and only the weaknesses of melcangi’s research were presented here and many were inaccurate
rat studies are definitely useful and certainly should not be ‘automatically disqualified’
i think it is important for the community to be open to the merits of different approaches and aware of the limitations as well
otherwise the group efforts will be led astray to some extent
3 Likes