Here’s the thread: The first Trial with SAGE-217
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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.
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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.
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Um. Allow me:
I’m not going to argue with you; I just want to say I’m frustrated we can’t agree about the obvious basics of our condition around here.
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It’s really hard to do that because there is so much diversity among people claiming to have PFS, there definitely may be multiple forms of PFS, and some ppl may be lumped in with PFS patients that have other problems unrelated to PFS.
We’ve identified a bunch of biomarkers in different studies. this is a multi-systemic illness so there will be a lot of interconnections that are going to be hard to discern and there may even be multiple causal factors required for PFS to develop in the first place.
Epigenetics seems very likely to be involved in some capacity though it is unclear yet in what way or how it may be treated if we identified a precise epigenetic issue. Some studies show biomarkers that are present in all PFS patients (like neurosteroid depletion) which warrants serious consideration and some show biomarkers present in some patients which would be more indicative of a correlation or indirect connection but definitely requires an explanation.
We have fairly strong epidemiological evidence and internal Merck evidence to show that this long term condition is real.
that seems to be the state of what everybody can really agree on today given the evidence. I happen to think there are a lot of strong causal mechanisms and evidence that show neurosteroid inhibition was a significant factor in causing PFS but there are strong reasons to believe that epigenetic modifications are involved as well. there isn’t enough evidence at this point to really say there is a clear path forward so I think it is foolish to close the door at this point on certain areas of explanation. I know people want to find answers and get to a cure as soon as possible but wishful and close-minded thinking will risk setbacks.
university research initiatives get corrupted all the time.
literally happened to us
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That’s like saying anger toward Merck is a biomarker of PFS.
Actually anger toward Merck is probably way more specific to PFS than neurosteroid depletion.
Anger is an emotion where allopregnanolone is a neurosteroid blocked by finasteride that was found to be undetectable in the CSF of PFS patients. I’m not sure what point you’re trying to make. If dht were undetectable in every single pfs patient in which it is measured (it isn’t), that too would be very notable.
So it’s better to follow all the ways indifferently and simultaneously? I agree with you in this.
We can’t figure it out what was wrong with us until we don’t try all the strategies
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.
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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.
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I wouldn’t say indifferently of course because you want to be smart about it but I do think it is far too early to point to a single approach. Makes sense to run different and thoughtful approaches in parallel until things can be narrowed down.
Epigenetic modification most certainly plays a role. Melcangi found methylation on the 5-AR in more than half of PFS patients. I just think that it is greatly underestimated how insanely complex that process will be found to be. Given how long it takes to get research done, there is a huge risk of multi-year setbacks by prematurely shutting down important research processes.
this specific community has adopted one avenue that they would like to pursue which is great but I think they’re doing the wider PFS community a huge disservice by speaking poorly of one of the most impt resources and researchers the community still has. it’s not an issue with the funding bc I’m pretty sure that any well thought out study will be able to get funding unless its insanely expensive, it is just the harmfulness of the message that concerns me.
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And where do we get the money for all this? It’s time to be realistic.
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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.
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