Altered methylation pattern of the SRD5A2 gene in cerebrospinal fluid of post-finasteride patients: a pilot study

Science PFS Research
#23

@pvdl The following physical symptoms were acknowledged:

“sleep problems, muscular stiffness and cramps, tremors, chronic fatigue, joint pain and muscular ache.”

I went to a urologist that acknowledged PFS, and I asked him about my shrinkage, hair texture change, and fingernail change. Symptoms to me that were irrefutable. He took a caliper to my testicles and determined they were normally sized. As far as fingernails and hair, he said he couldn’t acknowledge changes if he’d never seen them before.

So basically, we’re stuck in this weird place where we know our genitals have gotten tighter or smaller, but they are still within statistical norms. Idk how to evaluate these symptoms without before and after pictures.

Melcangi isn’t just acknowledging mental symptoms, he is acknowledging the ones I listed. I know it isn’t everything, but it’s a start. And just because he’s mainly looking at mental symptoms doesn’t mean that his research is useless. He’s pioneered a ton of important findings for us already and has continued to do so. I support his work.

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#24

I want them to try to explain the physical stuff, as thats the best starting point for any theory. If it cant explain the physical stuff its impotent, excuse the pun.

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#25

I see. Well the mental and physical symptoms probably come from the same place. I’m willing to put money that this methylated promoter sequence of the 5ar has effects on our minds and bodies.

Whether the methylation is cause or effect of PFS is another study or question.

#26

i dont know why exactly, but im extremely sure that my shrunken penis is a chemical process and not permanent. cause sometimes he is as big as before i have this deep trust

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#27

Just in theory what can be done to reverse this?

Discussion of 5-ar II gene methylation as an effect of AR overexpression
#29

@adrian two things come to mind.

  1. Genetic modification via CRISPR or another vector. Highly unlikely treatment and won’t be out for at least a decade or two. Also, only 50% of the PFS patients demonstrated methylation of this gene.

  2. Replace the neurosteroids that the 5ar2 in the CNS cannot produce. This is possible to test out via the allopreg injection infusions if allopreg is the culprit. 5ar2 takes progesterone and turns it into dihydroprogesterone. From there, more enzymes convert it into allopreg. Since 5ar2 is messed up, no allopreg is made. Thus, we supply our bodies with exogenous allopreg and other neurosteroids. This is the likeliest treatment from my POV since allopreg already exists. Brexanelone is the injection to try out.

I spoke to Phil from the Foundation and he said he is working with the creators of brexanelone for us to try out at low cost, or in a trial run. There is hope, boys! Keep the fire alive.

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Discussion of 5-ar II gene methylation as an effect of AR overexpression
#30

Well, the simple answer is they can’t. It’s a real pain when scientists try to dig in and fit a square peg in a round hole, and unfortunately they do. Carl Sagan wrote about the detriment of this. This characterisation of PFS is inaccurate and the theory that it is specifically targeted to the nervous system is already disproved. Di Loreto’s findings already established persistent (and more important) gene expression changes in the periphery. And no, this finding can’t explain PFS…at all. Wasn’t in all patients, men with genetic SRD5A2 deficiency do not have PFS (See Imperato-McGinley’s work that led to this drug). It also did not correlate to severity in either validated sexual dysfunction or depression scoring.

But don’t get your knickers in a twist. Luckily someone spent 1000 hours making a comprehensive survey based upon thorough literature review and every case in a decade and a half of patient self reports so patients can provide structured data and thus accurately characterise the syndrome :slight_smile:

Our survey will play a part in sorting this out eventually, but considering literature reviews (Than et al. 2018) are very clear regarding the physical effects, and Walf et al.'s 2018 analysis of 244 reports from this very forum note physical degenerative changes in a majority of self reports, there’s plenty enough there they will be well aware of. I’m sad to conclude there is an effort of distortion to try and reframe the syndrome to a theory, which will lead to a dead end precisely for the reasons you state. There is evidently not an appreciation for a pleiotropic picture beyond their area of focus. I recently found it a bit perturbing when @Demon’s most talked about symptom, for which he has urological evidence, was not included in a recent clinical profile by those guys yet their neurosteroid theory was.

But let’s be clear: Some of the speculation is tempered with extreme caution. He’s not massaging the data he is presenting, even if the speculation is off piste. So it’s nice to have. Additionally, they are not the only scientists in the world. So this is a plus. Funding decisions for future studies, or big sweeping conclusions, are not really relevant to this per se. It is what it is: More evidence of objective epigenetic differences in PFS patients.

Well…They are doing 10000 times more.

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#31

I am no scientist but it clearly says in the study that only 56.3% of the PFS patients had a methylated SRD5A2 promoter. Also in the healthy control group 7.7% had it too.

I want to know: how can this methylated SRD5A2 promoter explain the physical symptoms? Why does not the entire PFS subset have it, if all of them suffered from PFS?

Again it just seems to me that at best they might have identified a downstream effect of something else. I want them to explain exactly step by step how a physical symptom is born.

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#32

Good point. Its very important to have this information, so these guys finally accept that the physical symptoms are real, wide ranging, debilitating and more astonishing than the mental side. I mean think of it: How many medications destroy your facial bone structure, fat distribution, penile tissue and give you permanent fatique? Its astonishing.

I hope more people fill out this survey. One of the weaknesses of many PFS studies, due to the rarity of the symptom, is that only few can participate. If over time we had 500 people who filled out this survey it would be fantastic.

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#33

Yes, I acknowledge that only half the PFS users show methylation of the promoter. But that is statistically significant compared to normals.

However, this new finding that methylation in 5ar2 is frequently found in us aligns with the lowered neurosteroids found in us in this study:

Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, Melcangi RC: Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma. J Steroid Biochem Mol Biol 2015;146:74

So far, we’ve discovered lowered neurosteroids and abnormal 5ar2 gene function. This two facts go hand in hand, and to me suggest lowered neurosteroids are a solidified finding in us.

And lowered neurosteroids could totally cause our symptoms. The neurosteroids travel through our neurons and CNS/PNS which could impact fatigue, motivation, Sex drive, and penile shrinkage. I don’t know if neurosteroids could be responsible for skin issues such as elasticity, however.

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#34

Reading stuff like that I’m starting to think that PSSD and PFS are rather different. This illness seem to be turning all of you into girls. At the same time, I look exactly the same like pre pssd and nobody on Earth would tell I’m ill depending only on my look. And in case of PSSD ( I hope other sufferers would agree with me) mental symptoms are the worst. In majority of pssd cases body is still working almost the same, I can build muscles, play football and do whatever I want. Only one thing malfunctioning physically are my genitals. Mental sides are the ones which are literally killing us, unnatural anxiety, depression and so on.

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#35

@Snake Absolutely incorrect!
Nine days on paroxetine only and my body after one year is just falling apart.

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#36

Well, if there is differences, the survey should show them, and if there aren’t many, the survey will show it as well.

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#37

I have PSSD, but I have all phisical issues like Finasteride users… I have weakness, muscle wastage, cronic fatigue, I can’t play football, my skin is dry, my hair and body hair changed texture… I can’t explain! I never took an 5ar-i drug in my life.

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#38

I would say PSSD sufferers sometimes DO get the PFS symptoms. But with the emphasis on sometimes. I literally said this to someone else the other day: With PFS they seem to turn into girls, which doesn’t happen to most PSSD sufferers. My opinion is we both got genes silenced and fucked up endocrine systems. But i have the feeling PFS is more androgen related where PSSD is more reward system related. Both can look very similar and the solution and symptoms might be close to the same, but I do think there are some obvious differences. Things like boneloss and gyno aren’t things often talked about in the PSSD community.

#39

Whatever the case, survey says they are very similar conditions, which also surprised me regarding the reports of physical symptoms of PSSD that are rarely discussed on the PSSD forum.

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#40

Thanks, @axolotl . I read the full paper, and following are some quotes, which caught my attention:

  • Presently it is impossible to establish whether the SRD5A2 methylation pattern in PFS patients is set during early embryo development or results from finasteride treatment itself.

  • A possible hypothesis for the persistent side effects may be epigenetic modifications occurring in PFS patients

  • …demonstrating a tissue-specific epigenetic gene silencing

  • The reason for the persistence of PFS symptoms even long after drug withdrawal in PFS patients remains a mystery.

  • These results, however, must be interpreted with extreme caution, given the low number of subjects analysed

  • Whether the sexual and psychiatric symptoms documented in these patients are related to methylation of SRD5A2 cannot be concluded by this study, as no significant differences could be demonstrated

Roberto Melcangi is clearly telling us to not read too much into these results. As he states, these results do not directly explain anything, let along point to a root cause. So let’s all refrain from interpretations, which the author of this paper does not support.

Having said this, I find the results where many patients have SRD5A2 methylation intriguing. Though, I am looking at this from a completely different angle, than what RM was hypothesizing.

DNA methylation plays an important role in regulating gene expression (of any genes, not just SRD5A2). Aberrant DNA methylation is a feature of a number of important human diseases. The addition of methyl groups is controlled at several different levels in cells and is carried out by a family of enzymes called DNA methyltransferases (DNMTs).

Since a while, I am suspecting that perhaps a mutation at the DNMT level and/or methyl donor excess could be involved in this, in the sense that we are more sensitive to epigenetic modifications triggered by endocrine disrupting substances, than your average person would be.

This could explain the persistent overexpression of the AR, which was found in PFS patients examined in the 2014 Di Loreto study. Such a hypothesis makes a lot of sense to me, with deregulated neurosteroids, 5ar, gut microbiota, etc. as a downstream effects. It is hypothesized, that persistent AR overexpression is also caused by epigenetic modifications at some level.

AR overexpression can comprehensively explain our symptoms, while the purely CNS focused view of RM cannot. Perhaps that is why he is largely ignoring the vast physical symptom profile outside of nervous system related effects, which I don’t really consider good science. Even if he cannot explain them, RM could at least acknowledge their existence. By not doing so, he unfortunately is cementing an incomplete impression of what PFS is, and is thereby doing us a disservice. Having said this, I appreciate the work he has been doing regarding PFS, even if I do not agree with his narrow approach and many of his views.

In summary, this paper gives us further clues of where to continue looking. By this I don’t mean more focus on the brain, but rather on epigenetics and the methyl system, mainly also outside of the brain.

Note: These days, whenever I mention PFS, I am always referring to the bigger picture of PSSD, PAS, etc. I consider these to be the same problem, until proven otherwise.

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#41

On where not to continue looking, as the question “is downregulation of 5-ar type I and/or type II the source of this syndrome” has been on the minds of many over the years regarding both Propecia and Accutane.

I think that is one positive to result from this study. We can practically lay the 5-ar theories to rest.

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#42

Very hard to state that something is “statistically significant” if only 16 PFS sufferers participated. The doctor I know would laugh me out of the room if I made such a claim. Actually that was one of the main complaints about all the PFS studies he looked at. Its just very hard to get to a decent sample size if the affected community is so tiny.

#43

Yes, that should have been part of my list as well. In the past, many have speculated that finasteride somehow permanently “nuked” 5ar. RM is clearly not of that opinion:

The molecular mechanism of 5α-R inactivation by finasteride is known since two decades, likely resulting in persistent enzymatic inhibition over time, but this does not fully justify the long-lasting alteration of the neuroactive steroid levels

RM is a well known 5ar specialist (in the context of the brain), so this question is squarely in his field of expertise.
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