Back to the basics

General Discussion
#1

Can we please have a conversation going back to the basics? WE SHOULD SUPPORT PFS RESEARCH to speed up things, but I hope we can try to have some conversations on the issue on our side too. I believe this is as important. FYI I am a researcher but in another field (if that helps my credibility at all, have a PhD and I am a mature and very sensible guy so please hear me out :slight_smile: …)

I just heard the interview with Dr Yu which is key, because it goes back to the basics. They discuss the up regulation of receptors. My first reaction was similar to Dr Yu, the causality could (most likely) be from low androgen to up-regulation. That is she seems to think that our symptoms might not (most likely) be due to an up-regulation. For example, they could be due to lower androgen reaching these organs (something my Doctor said, they can just test circulating) or due to some aging of the ograns (which would be a disaster), or a lot of other possibilities.

I have an important observation to add. The lack of libido, the loss of sensitivity, and ED are not special to 5alpha-reductase inhibition I think they can be caused by any form of lower andorgens/DHT either directly or indirectly. I say this because someone I know got THE EXACT symptoms after being on an anti-androgen. He never touched Finasteride, SP, or other. I think that helps narrow down the mysterious channels. While the inhibition of 5 alpha reductase could be the direct cause of a lot of the mental issues, our sexual symptoms, including this weird numbness and changes in texture are most likely due to androgen deprivation. He also recounts a story of him crashing after stopping the treatment.

So that is one thing we all have in common. The way it happened to me is that when I stopped Fin, I had two weeks of VERY high libido, I was ejaculating every day which I have not done in years, for almost 10 days in a row. Then came the crash.

So androgen increases but receptors are still up-regulated due to a lag, this is the feedback loop story. And then what? Million dollar question – what causes the crash…

Here is another important observation: A lot of us become EXTREMELY sensitive to any form of androgen deprivation. Case in point, yesterday I applied Eucapil to my hair, this is a topical agent that is supposed to bind to the androgen receptor ONLY topically (I will double check the details) and I suddenly felt like crap, numbness increased, libido dropped from 0.5 to 0. I have used it for years, sometime 4 capsules at a time, this is a drug that is marketed as having ZERO systemic effect because of the way they deliver it, it gets converted to basically water in the blood. All this to say very small decline in androgen or in functioning androgen receptors leads to a big effect on us. This has zero effect on a healthy patient.

#2

following up on my post, based on the facts I discuss below, it seems to me that we cannot rule out that our upregulated ARs are not doing their job well, i.e., transcription factors, mutations,…, here is a para from Wiki about possible mutations that could lead to androgen insensitivity.

But here is my speculation 101 now:

  • ARs are upregulated no longer because of lack of androgen but because their transcription is less efficient, something is not working well.
  • So if you do anything that would downregulate ARs (Such as T therapy) You FEEL WORSE, because the ARs need to be working at maximum potential to get the bare minimum transcription going… The same goes if you reduce their activity directly (my example of Eucapil)…

WIKI

The androgen receptor gene contains two polymorphic trinucleotide microsatellites in exon 1.[2] The first microsatellite (nearest the 5’ end) contains 8 [17] to 60 [18][19] repetitions of the glutamine codon “CAG” and is thus known as the polyglutamine tract.[3] The second microsatellite contains 4 [20] to 31 [21] repetitions of the glycine codon “GGC” and is known as the polyglycine tract.[22] The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.[23] In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer,[24] hepatocellular carcinoma,[25] and intellectual disability [17] are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more.[26] Some studies indicate that the length of the polyglutamine tract is inversely correlated with transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility [27][28][29] and undermasculinized genitalia in men.[30] However, other studies have indicated that no such correlation exists.[31][32][33][34][35][36] A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved when sample size and study design are taken into account.[11] Some studies suggest that longer polyglycine tract lengths are also associated with genital masculinization defects in men.[37][38] Other studies find no such association.[39]

AR mutations
As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow.[2] Inheritance is typically maternal and follows an X-linked recessive pattern;[1][40] individuals with a 46,XY karyotype will always express the mutant gene since they only have one X chromosome, whereas 46,XX carriers will be minimally affected. 30% of the time, the AR mutation is a spontaneous result, and is not inherited.[10] Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself.[41] In one study,[42] it was found that 3 out of 8 de novo mutations occurred in the post-zygotic stage, leading to the estimate that up to one third of de novo mutations result in somatic mosaicism.[1] It is worthwhile to note that not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14 percent of genetic males,[43][44][45][46] and is thought to adversely affect only a small number of individuals when other genetic factors are present.[47]

#3

A study related to my first point in first post:

ncbi.nlm.nih.gov/pmc/articles/PMC3992475/
“We have reported previously that finasteride interferes with DHT binding to AR, reduces DHT-stimulated AR activity, and depresses DHT-stimulated growth of LNCaP cells [4]. These findings suggest that this AR inhibition by finasteride is independent of its ability to inhibit 5α-reductase.”

#4

Interesting musings. I wonder if some of the better researched members of the forum (such as yourself) could be collaborating with the scientists on this. Even a one time meeting (Skype?) between several of the “brains” here and scientists working at Boston or Harvard might lead to something. It might sound crazy but all it might take is a few like minded people to hash out a successful theory. What do you think?

#5

I agree that we should talk more with scientists and not just from the sponsored clinical trials. If anyone wants to cooperate on sending well thought gentle emails to some reasearchers about our case, tell them that some data are already available, tell them that we have a population that is reading to do testing and has been doing, and so on.

The reason this could be very productive is that we are in an area very close to the research on prostate cancer which is decently funded. So there are a lot of scientists out there who work day in day out with anti-androgens and receptors, albeit from a v ery different angle, who might be interested in staring a new line of research.

On a related point, but also could be very relevant on its own I was watching the following presentations:

[youtube]https://www.youtube.com/watch?v=OmwZwiiL61U[/youtube]

At 4:40. What you will see is a well documented case in SOME cancer patients of a Antiandrogen withdrawal syndrome of what she calls a paradoxical withdrawal, in which once they quit the anti-androgen therapy the PSA levels (which are typically high when circulating androgen are high) DROPS. They say this typically happen somewhere between the treatment is stopped to about 4 weeks after…

I thought it is interesting, might have to do with a similar paradoxical shock that we experience …

People in the know let’s get in touch…

#6

First things first, how about we draft some veteran members of the forum who have the most knowledge about pfs, with a diverse background and perhaps several theories about causes (even conflicting). Any suggestions? Once we have a group of people, they can have an initial chat and seek researchers either already working on pfs or independent.

So let’s start with you, numbduck. Who else to add? Ideally I’m thinking 5-6 people.

Maybe this is crazy but it’s possible that putting the right team together - pairing brains from the forum with scientists and researchers, may lead us somewhere. This isn’t to take for granted any of the work already being done either :slight_smile:

#7

Thanks nopecia. I think the idea is a good one and i would like to help implement it. I believe every small effort counts.

I am however relatively new to the site. The site has been up for 10 years or so, so i need veterans to guide me on where the knowledgable sciency veterans are.

I wait for recommendations from you, moderator or anyone who knows who would be a good candidate…

#8

We should call at least some medical students here. They have more time to help us and more open minded than doctors.

#9

Maybe I could start a new thread to ask everyone. Once we have a team we can talk about our actions. I’ve definitely been impressed by contributions of people who’ve posted here over the last couple of years, so let’s put those guys together, pool our ideas and see what happens.

#10

Sorry but I don’t think this would be a valuable use of researchers’ time. The studies are taking their own carefully-devised path and there is no way we are going to advance the research by having an internet chat.

#11

This isn’t the 90’s, the internet is as valid a way as any for people to collaborate. Indeed, the studies were a result of this forum in the first place and I am sure there are a few guys here whose knowledge on this topic rivals the researchers. Why? Well some of us are already very well educated and this isn’t about our livelihoods, it’s our lives. One conversation could spark a chain of events that cures this. Why rule anything out at this point? I’m not suggesting myself for any of this for the record. I am talking about nominating a team of representatives with the best knowledge to talk to researchers in the relevant fields and brainstorm.

#12

That’s what the PFS Foundation is doing. They have the authority, backing and connections to make things happen.

#13

True. Do you think that some of the knowledgeable members of the forum could contribute somehow? There may be some untapped potential amongst us. Just a thought.

#14

Nopecia was not suggesting this in anyway as a substitute for research, that would be crazy, he is saying that in addition it would be important for us to discuss these things between us - which is what the forum is partly about. The novelty here is that he is proposing for the sciency people to get together and talk on one thread, about ideas, theories, …

He is right that there are some really knowledgable people around and would be good to bounce theories and ideas with them…

Yes it might not lead anywhere, but still worth it for people like us…

#15

Cheers numbduck. You’ve got it and I agree it can’t harm to supplement what’s already being done. The hardest part will be figuring out who the most knowledgeable people on the forum are. Should I create a separate topic and ask for feedback?

#16

Numbduck, do you think we have 5ar receptor damage or deficiency? I searched 5ar deficiency symtpoms on net but didnt find big things.

#17

Nopecia sounds a good idea. I agree it is hard, people come and go but let s try. Let s call on the biologists and endo-geeks to identify themselves and let s keep the discussion moving.

Depressed guy, short answer i don’t know, but as i suggested earlier another hypothesis that has merit is that 5ar is not what is causing the sexual dysfunction but rather the problem is at the androgen level and the receptors, the latter most likely given the normal results for many here. I discuss my thoughts above.

#18

By the way I agree with your idea about the signature thing. I just joined a forum for Chronic Pelvic Pain Syndrome and it’s pinned that members must offer a description in their sigs.

Here is the post:

Copy and paste the exact code below into the signature area of your profile, and fill in the missing details. Do not remove the formatting codes.

[color=grey][size=85]Age:  | Onset Age:  | Symptoms:  | Helped By:  | Worsened By: | Other comments: [/size]

It would probably help us understand each other a little quicker.

#19

The Theories section already exists and is littered with dead end theories, red herrings etc from armchair scientists for nearly a decade now. Personally I’m done with theorizing, I leave that to the scientists who have the education, knowledge and abilities to investigate the root causes of why Finasteride causes side effects to persist. Hence why studies are underway. If you’d rather discuss yet another theory, feel free but do not let it detract from the real goals – raising media/social awareness of PFS, holding the drug company accountable, contributing funds towards future research and the PFS Foundation.

#20

Agree with Mew, to many people are jumping to conclusions based on their own crash experience. Best to just participate in official research. I got my appointment at Baylor. How about you? Help us close out this round of official research so we can move on.