Methylation: What is it?

Hi all. This topic is about the word of the week: Methylation.

You will have seen the word being posted a lot lately owing to the recent finding in PFS patients, with study abstracts posted, and “demethylating” mentioned. I regularly say and will reiterate at the outset that for those really wanting to engage with the scientific issue seriously, time spent googling keywords or searching posts with a confirmation or survivorship bias is far more practically used taking basic endocrinology, genetics and epigenetics courses or pursuing a structured self-education with up to date and reputable academic materials on pertinent subjects. However, this is just to give interested members who want to quickly get an idea of what methylation means that in a nutshell. As such you may already know all this. As I have had to explain what it is a few times, I thought I’d make a quick topic I can point to as it’s likely to be relevant in the future.

Something @awor has been talking about for over a decade is that epigenetic mechanisms are involved in PFS. Epigenetics simply means the field of study regarding factors, environmental or endogenous, that alter the expression but not the code of the genes within individual cells. It is likely becoming clear to anyone following the research efforts that evidence is mounting that the pathology involves epigenetic dysregulation of a site-specific nature, differing in severity across patients and affected sites within those patients. Here’s me bringing this up over a year ago:

It is the view of the administrators of this site that persistent changes to gene expression are the only plausible driving factor underlying PFS, which is a manifestation of the broader Post-Endocrine Disruption Syndrome we see occurring after use of diverse antiandrogenic substances in a subset of consumers. In recent years, Di Loreto confirmed significantly higher expression of the androgen receptor in all patients, and Melcangi recently reported methylation of SRD5A2, a gene coding for the 5 alpha reductase type II enzyme, in the cerebrospinal fluid of over half of PFS patients considered. In a poorly reported appendix to a study including assay of nonsymptomatic tissue, Basaria et al. mentioned finding some significant differences in some androgen regulated genes that did not share an identical cluster on hierarchical analysis. We expect further findings in Baylor’s epigenetic investigation which has proceeded with previously validated genital skin. Conclusively, lasting differences in gene expression are observed in controlled study of PFS patients.

Methylation is one way (along with many other factors including ubiquitination, acetylation and phosphorylation) that gene expression is controlled. Methylation patterns are initially set prenatally. Patterns comprising the methylome are (somewhat) stripped from male haploid gamete and replaced by the egg when they together form a zygote, putting the epigenome in a totipotent situation. Sadly, in the context of powerful endocrine disruptors, the sins of the father are not always so escapable. Vinclozolin is an example of this. Finasteride is likewise categorically an endocrine disruptor and exhibits negative effects transgenerationally in animal models, despite the claims to the contrary you’ll find on sites selling it.

A gene is a nucleotide sequence that codes for a functional protein molecule. Chromatin packages DNA up small to fit in the nucleus of ᵘʳ ᵗᶦⁿʸ ᶜᵉˡˡˢ. Chromatin is composed of histones, which DNA wraps around. How tightly closed this is in certain areas is an important determinant of gene expression. Methylation can be acquired in somatic cells, modifies chromatin, and thus alters the access of proteins that bind to DNA (transcription factors). Methylation is what is called a repressive modification. This means that the more methylation there is in a CpG island (an area in most gene promoter regions often denoting the start of a gene), the more repressed the gene. Like a dimmer switch. Additionally, CpG islands can be found in intergenic regions. During cell division and replication, the methyltransferase enzyme DNMT1 maintains existing methylation while the enzymes DMT3a and 3b establish new methylation. To be clear, methylation is crucially important in like…not being a pile of soup…and 80% of mammalian CpG islands are methylated to some degree. Some areas of the genome are shut down entirely. Methylation is also very important to cell differentiation. To be slightly technical, the DNA base 5-methylcytosine is formed through the attachment of a methyl group to the 5th position of the cytosine ring in a CpG dinucleotide. Methylation is therefore by its very nature a question of degrees - the more the merrier - and such degrees of difference provides a compelling explanation for the vast difference in affected sites and severities between patients (e.g. why some have a functional impairment like anesthesia while others will experience severe atrophy), and why additional persistent symptoms are noted to develop in PFS/PSSD/PAS patients following further endocrine disruption.

Proven significant epigenetic differences in pfs patients with genital pain and atrophy (Di Loreto 2014) were on average 5 years after cessation would rule out transient modifications in severe cases and it’s unfortunately the case these changes will be being passed on to daughter cells. Traish’s 2018 paper, The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption discusses this finding and proposes his idea of how mechanistically epigenetic changes could be occurring and leading to PFS in predisposed patients.

The effects of inhibitors of this process are more significant in the frequent application of cancer, as cancer cells divide much faster than other somatic cells, so are vulnerable to the interruption of DNMT1. In the context of PFS and the use such drugs to address deleteriously methylated loci in somatic cells, it remains to be seen whether something this nonspecific could be taken for a long enough duration without adverse effects in the rest of the organism, a worsening of PFS, and with any positive effects at all. It is also important to consider that adult neurons do not divide, so the usual interruption of enzymatic process is not going to be applicable in the CNS. Although DNMT enzymes are expressed in postmitotic neurons and there is some evidence of HDACis inducing what is referred to as active demethylation, it is not yet clear exactly how they mechanistically regulate neuronal methylation.

Not the most up to date, but this review covers a broad amount if you’d like to read more.

For a very readable overview of epigenetics I thoroughly recommend The Epigenetics Revolution by Nessa Carey.

Hope that’s helpful


Thanks for the summary.

Seems like an almost impossible thing to fix.

Are you saying our children will suffer from PFS-like symptoms?

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I would like to comment that the problems u describe with current chemo demethylating agents not being active in non dividing neuronal cells, are problems not seen with the demethylating agent RG108.

‘’ we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N ‐phthalyl‐l‐tryptophan (RG 108) was injected subcutaneously in rats.’’

If u are interested in the substance and the story behind it, this is a very good read:

Permanent changes in human gene expression from just one pill or like the recent guy said (which I’m not all sure what to believe) 1/4 of a pill is a little hard to buy into.

For me, these rapid changes in gene expression could possibly be explained, the keyword being possibly, by rapid microbial shifts.

Unlike the human genome, the microbial genome is rapidly modified through diet and drugs.
Microbes in turn could affect human gene expression.

October 26, 2016 / Genomic Medicine

How Trillions of Bacteria in Your Body Can Change Your Genes

I’ll also throw in this really simple concept.

Microbial endocrinology: the interplay between the microbiota and the endocrine system

The new field of microbiome research studies the microbes within multicellular hosts and the many effects of these microbes on the host’s health and well-being. We now know that microbes influence metabolism, immunity and even behavior. Essential questions, which are just starting to be answered, are what are the mechanisms by which these bacteria affect specific host characteristics. One important but understudied mechanism appears to involve hormones. Although the precise pathways of microbiota-hormonal signaling have not yet been deciphered, specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produces and secretes hormones, responds to host hormones and regulates expression levels of host hormones.

Thanks for your efforts btw.

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It really is.

Also I am still not understanding how the symptoms are actually caused. Epigentic change, androgen receptor overexpression, site specific alterations etc. At the end it seems very vague still.

If most PFS patients had an overexpression of the androgen receptor shouldnt it be easy to test and prove? If this is an important cause, shouldnt we be able to explain how it causes physical changes for example?? If it were so significant, shouldnt this debate be over already?

Can anyone present an exact causal, step by step, explanation of symptoms like penile shrinkage, jaw wastage, fatique, etc etc? Or is this all correlation in correlation out mental gymnastics?

I know it seems like an absurd question, but at times I have the feeling that you moderators already believe that you know whats causing this. Then present an Input (finasteride) to OUTPUT (symptoms) explanation (i.e. a causal explanation not a correlation theory). What do you actually know and what dont you know? At what part of INPUT (finasteride) OUTPUT (symptom) do you still have a stumbling stone? What is the problem? If you had a very compelling causal theory, shouldnt you be able to prove it in a study conclusively?

If Baylor, a study co-designed by awor, does not push us forward in a significant way, will it mean that your understanding is much more limited than you thought?

I am not trying to be confrontational. I am just seeking some clarity here.


This is the entire point of the PFS research!!! Not sure if you are calling the admins/mods out for witholding key information about PFS that we don’t yet have?

And FYI, 1/4 mg of finasteride inhibits DHT by around 62% and 5 mg by around 70%. Would you be more inclined to believe some members here if they said they took a week’s worth of 1 mg pills vs 1/4 or 1/2?

No, I am not. I am trying to understand what causal theory you are trying to prove with the research? Do you have a causal theory as I described above?

Thanks for having some faith in our good intentions. :slight_smile:

The theory is laid-out in awor’s “5-ari-Withdrawal Syndrome” paper and supported by Melcagni’s research showing lowered neurosteroid levels in PFS patients and Di-Loreto’s study showing persistent upregulation of AR in penile tissue of PFS patients.

AFAIK, Baylor may bridge the gap between drug and symptoms if they find androgen-responsive genes are being aberrantly expressed in PFS patients.

It would be nice if someone could write up a summary of the causal theory in laymens terms (much simpler than what axo did above, with more definitions etc). Also what are the gaps in the causal explanation chain? What results would dissprove the theory? Like 6 year old terms. If you had to explain it to a patient who is illiterate with medical terms etc.

So if Baylor is a nothingburger the theory can be laid to rest? After all awor helped design it.

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It would be nice to have a graphical representation of the theory made for the purpose of explaining it. Picture is worth a thousand words. Unfortunately, the admin/mod team is so inundated in regards to our volunteer work, professional lives, and personal lives, this will not likely happen soon. Generally speaking, we are like anyone else here dealing with keeping it together while suffering.

The hypothesis wouldn’t necessarily need to be abandoned if Baylor publishes no significant results. The hypothesis may be modified to exclude what Baylor was specifically investigating.

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I suppose Baylor, if it supports the theory will simply add to the ammunition. Upregulation of AR is already proven. Causality will be harder to prove though it would be highly unlikely if it weren’t causal. I’m not entirely sure what Baylor will add in terms of utility other than highlighting which epigenetic changes have taken place… and perhaps trying to find the modification which may lead to excessive AR expression.

Hey guys, this topic was only to briefly explain what is meant by methylation, which has been proven and reported site specifically in PFS patients already. Theories are therefore not relevant to the content here as this is just a basic mechanism of cellular biology. This ties into a broader framework most users don’t have, so therefore might be handy as it’s unlikely the last you’ll hear of it.

Regarding theories, the microbiome is almost certainly disturbed in PFS as both ADT and tissue AR dysregulation is proven to do so. I’ve linked to a study regarding this some time ago that I believe you recently posted. That is therefore supported by evidence as a plausible consequence, of which there are many, and is not a site-specific cellular mechanism nor is it capable of causing what we have seen for the past fifteen years.

@pvdl, as I’ve said we’re working on a project that should hopefully answer all your questions, but it’s taking some time as it has to be robust and comprehensive. There’s a lot to cover and it is simply not suitable for a forum post format. There’s a lot of recent science we haven’t discussed (as I’m considering submission to peer review) that we feel very significantly ties into the bigger picture. And whether you find it hard to believe or not, many of the most severely affected members took one pill or less. This includes myself. While a single epidemiological study of 5ari use in general found length of use of 5ari to increase risk of lasting erectile dysfunction, every single study of PFS that profiled symptoms with validated and as hoc instruments concluded that severity had no correlation to exposure in their samples. The entire reality of a post drug syndrome is out of the realms of what makes “common sense”, so I find it quite incredulous when people with at least some degree of lasting effects start picking at other members because to them it seems rather far fetched to them. Your case does not seem any less far fetched to the millions on this drug with no significant detrimental consequence to their quality of life, otherwise your doctor would be up in arms and no one would take it. It’s important to bear in mind there is obviously something different about susceptible patients, and significant variation within that. Many years ago Crisler phrased it as there being something about our endocrine systems that “is all set up to get broken” when he was explaining that he was repeatedly seeing patients with PFS who did not respond to treatment, and in layman’s terms that’s the long short of it. Precision medicine study by Cauci et al already correlated both exposure and PFS symptoms/severity to AR polymorphisms, so the “something” I mention is likely to be genomic, epigenomic or both. That’s why we’re taking a look at what we can ourselves with the 23andme project. It’s a serious long shot, but it’s worthwhile in the meantime.

Let’s keep this topic on track now as others can be started regarding unrelated stuff or theories.


Looking forward to it. I would suggest that it’s incredibly important that a detailed summary is posted on propeciahelp, explaining the causal theory you guys are working with in Layman’s terms, so that even the average visitor to this site, who is not immersed in the scientific literature and doesn’t understand even basic medical terms, can understand it.

I. E. Finasteride intake causes A which causes B which causes C which causes D which causes symptoms, in person susceptible to PFS. Our research is focused on proving out step b to c for example or filling in following blank. Pls donate to this current study to achieve this. And then a link. As suggested above this page could be enriched with nice visuals. It could also list outcomes that would disprove the theory etc.

Pls no correlation in correlation out stuff.

I need to clarify a few things real quick.
First when I use the terms believe or hard to buy into, I was talking about permanent changes in human dna from one pill. I wasn’t talking about being affected from just one pill, Im not questioning that.

Also when talking about methylation, I think this could still fall into the realm of Gut homeostasis.
On the microbiome I think I could challenge this thought based on my own experience,

But this is coming from Accutane not Fin (maybe more of a one trick pony where its very easy to zero in on hormones)
Accutane can change the expression of literally hundreds of genes.There’s also probably alot more wide ranging studies on Accutane and even retinoic acid itself then Finasteride to come to different conclusions or have different thoughts.

Accutane has been shown to have powerful immunomodulatory, antibiotic, and hormonal properties as part of its mechanism of action. As far as a 5ar inhibitor (or hormonal), I thought this effect was rather weak compared to the others just mentioned.

Anyways to post another thought back on topic, just because we haven’t been able to treat this yet, doesn’t mean it might not play a major role.

Gut Microbiota as an Epigenetic Regulator: Pilot Study Based on Whole-Genome Methylation Analysis

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I have a question if I may and if someone does have a time/mood to answer - why do some sufferers clearly purely benefit from methylation/taking methyl agents (even some recoveries), while others from demethylation (this makes sense)? Sorry for spamming if it is explained here, I already guess it has been answered, but those large blocks of text are sometimes overwhealming for my congnition, even more after a hard day… and thanks in advance

My guess is because not everyone gets the same genetic alterations. Maybe for some, silencing of genes is the main problem, where for others overexpression of genetics is causing the struggle. This is just a thought tough.

Thanks for the reply, but I kind of thought it may be like that, but still doesnt make much sense to me… shouldnt the syndrome causing meds be having more or less same mechanism of action on everybody? Either silencing genes or somehow overexpressing them? Probably (dull) question for the more knowledgable on this forum, but still interesting and important for the less knowledgable :slight_smile:

By the way, I for long wanted to do some gene testing like MTHFR, is it useful in practice? Will it somehow help me to know if I should avoid x, y, z or do x, y, z - or is the test kind of waste of money in regards to the syndrome and its treatment? Will it be useful to this whole methylation/demethylation issue on personal level - for me to know the results, help in treatment itself? Prevent crashes (ok, I am taking this too far… :D)? Thanks for insights in advance

Personally, it’s all fine with me. Epigenetic damages or not, gene methylation or not, BHB, Keto and fasting helping or not.
I get that our DNA is rolled up in every cells as a compressed file on a computer, with only a few segments unrolled so that the cell can use them and that’s what epigenetic is about. Otherwise it would be unpractical and would probably mean death.

I’m less active on the blog because I don’t have much symptoms left after 13 months of carnivore / ketogenic diet (or at least that’s what I attribute it to with an almost certainty) and I feel better than I did in the last 20 years.

I’m a company owner, there’s a HUGE financial crash coming within 2 years, one that will dwarf the 1929 depression and I will most likely lose my factory. Having 3 kids and a wife and living in a foreign country with no security net, I’m now spending all my time studying economics and finances and trading on forex and stock markets.

I believe the Universe is alive and that it interacts with us, especially when it’s important and we pay attention. I asked the Universe for a remedy to my crippling pfs and coincidences after coincidences, I ended up with a strict carnivore / keto diet and weight lifting. 13 months later, I’m better than pre-fin.

So this is the kind of guy you’re dealing with when you address me. If you don’t believe in that kind of shit, by all means, just dismiss me and ignore the few posts I’m writing. There’s actually science behind my “Universe is alive” claims but here is not the place to debate this and frankly, from my point of view, it changes nothing what you believe in (except for feeling sad for those who believe (and it is a belief) the universe is dead and things happen randomly. I can’t imagine the feeling of loneliness and isolation that belief would bring but it’s not my place to judge).

I’m not pushing any ideas on anyone, just sharing honestly what I believe in, mostly with regards to fighting pfs. It’s up to each of you to integrate or dismiss what you see fit or unfit. But I do wish you all the best and I hope sometime soon, we’ll find a way to counteract the damage done by those drugs.


Thanks Ozeph for a very nice post. And couple things related to this condition brought me to the rock bottom in many ways and I even did multiple Ayahuasca treatments and believe me when I say that I know EXACTLY what You mean, it changed me to much better person - for good. Universe IS alive. Thanks for Your kind wishes and I wish You the same and good luck also in upcoming financial crisis, hopefully it will turn out good for You and family anyway somehow. Good luck and strong health Ozeph

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Hey by any chance did you take the pill on an empty stomach?