A proposed etiopathology of persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors: Sequelae of drug-mediated microvasculopathy, Montaigne 2022

Montaigne, M. (2022, February 11). A proposed etiopathology of persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors: Sequelae of drug-mediated microvasculopathy. https://doi.org/10.31219/osf.io/86cnm


Persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors (PD-5ARI) may be explained as the aftermath of a pathological recovery from microvasculopathy or ischemia in multiple systems. Focusing on persistent sexual dysfunction, the most common class of symptoms: 5ARIs’ inhibition of angiogenesis leads to stress on penile microvasculature, depriving the tissue of blood supply and oxygen. These hypoxic conditions lead to tissue injury and atrophy, triggering a pathological recovery that further alters penile tissue, including smooth muscle loss, fibrosis, damage to vascular architecture and impairment of neural pathways supporting arousal and erectile function. This damaging cascade may result in severe and lasting sexual dysfunction. Persistent neuropsychiatric, cognitive, sensory and sleep dysfunctions emerging from 5ARI treatment may similarly be explained as pathological responses to microvasculopathy or ischemia in supporting structures, particularly those in the limbic system. Systemic spread is proposed to arise from a vicious cycle of tissue injury, oxidative stress and proinflammatory activity which spreads via the vascular network, leading to systemic endothelial dysfunction. The latter may in turn set off a damaging cascade in other organs and tissues. Risks of developing PD-5ARI may arise from 5ARI-mediated disruptions of vascular tone, angiogenesis and neoangiogenesis. Pharmacovigilance data, animal studies and human studies provide converging evidence for the proposed etiopathology. It is, moreover, consistent with variable presentation and severity of PD-5ARI symptoms; irreversibility of symptoms; typically normal results of clinical lab tests; and resistance to treatment.


this article has not yet been accepted by journals, the author is a pseudonym with PFS… I do not understand if it should be published, what do you think?


How to explain breast development? And body odor and hair changes? I think this is an article of “blind people touch elephants”, which may reveal some things for us, but it may also lead us astray.

This is my point of view

thank you very much for posting it


Well this is depressing :frowning:

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This has been posted elsewhere previously.

It’s not very plausible to suggest that stress on microvasculature and resulting hypoxia could cause symptoms such as anhedonia, loss of libido and sexual desire, reduced ejaculate volume, watery ejaculate, and others. It also doesn’t explain the brief period of recovery reported by the vast majority of our survey participants before their crash. Further, it doesn’t explain how it could cause specific changes in gene expression as discovered in Baylor.


I don’t wanna disagree (for more or less obvious reasons) here, but the most overexpressed gene clusters in Baylor was: skin development, then significantly more expressed were: cellular response to oxygen levels, tissue migration(including tissue remodelling) and surprise response to steroid hormone; top under expressed gene cluster was blood vessel development. Those gene cluster are not perfectly indicative of what is happening one to one, but you can kind of get more specific if you check subgroups in those clusters. And the bigger picture which you can infer seems to fit the title of this preprint. (What I did is I accepted the title of this preprint, went to Baylor results and checked if this thesis fits the Baylor picture, so if any genes are obviously pointing to this and I have ignored gene clusters with mysterious names that I don’t understand)

To the point of this gene expression changes do not explain anhedonia, loss of libido, etc. Well those samples were taken from genital skin, not brain, spinal cord, seminal vessels and probably do not reflect changes in those tissues. And if this is really the cause of PFS then perhaps the Tampere study could probably show some shared genes related to hypoxia or blood vessels?

(Btw if I was not severely emotionally blunted I would cry while writing this, also I am getting scared reading this preprint). I hope I am wrong and somebody can somehow rebut this.

Also the author seems to have answered some questions here. https://www.researchhub.com/user/504016/overview

There is one mistake: To look for the explanation (rootcase) for pfs in the blocked 5ar enzymes.The blocking of the 5ar enzymes has directly nothing to do with pfs. Maybe it sounds total stupid and unscientific. But that’s even the mistake of all the existing animal models too.


2.3 million Americans are on finasteride for years with blocked 5ar enzyms and they have nothing or only temporarily sides from the secondary hypogonadism. After quitting the SRD5A… genes produce new 5ar enzymes to the normal level after some weeks again. DHT leves increase, AR leves decrease to normal again. The long term effect of finasteride to a not prediposed man is zero. As hard it may sound for us!

Only a small percentage of men develope the post drug syndrome from a disabled feedback DHT increases -> decrease the biosynthesis of the Androgen receptor genes.

So all the 3800 altered gene expressions and the consequences to all functional clusters have nothing to do with finasteride, but with the finasteride caused feed back to the androgen receptor genes or to an other potential root case.

In so many discussions the direct consequences of finasteride blocking 5ar or are listed as root case or other finasteride altered functional systems are mentioned as the rootcase causing the 3800 altered gene expressions indirect by neuroinflamation or oxidative stress.


In my comment I did not really consider that blockade of 5ar in humans will cause PFS nor did this preprint. I just wanted to comment that it seems likely(ish) at least for the genital skin that some specific changes from Baylor can realistically stem from the proposed mechanism in preprint. And my point would be why the root cause mechanism for all the symptoms would be different? The question on ‘why us’ is still unanswered as some other important questions.

Also another point that comes to my mind is that all the fin treated rats seem to develop PFS like maladies and only small percentage of men get PFS. Could this be some clue or I am wrong about rats?

Also2 could this explain post aromatase inhibitor syndrome?

I was reading several tweets from Antonie Csoka who is a Asoc professor at Howard University and has wrote several papers on epigenetics and some awor used to reference here heavily…Especially those pertaining to pharmaceutical products affecting epigenetic changes in people…

He basically was hypothesis for how finasteride might cause the changes in gene expression…

It was through chromatin changes or alterations to the chromatin from various different methods but basically said the reason u are not affected the fist time or after the 2nd exposure or cross exposure from finasteride or another drug like Accutane you may have taken years before is that it only slightly alters the chromatin the first time…it maybe then severely altered after 2nd exposure in a fragile state…And a bunch of shit is triggered to gene promoter regions, enzymes and stuff I don’t have the first clue about that methlaytes these genes silencing transcription…

I think those epigenetic changes especially if you get PFS finally happen because some mikro or makro mechanism gets triggered or pushed over the edge. The main question would be what is the mechanism and is it reversible by crispr/cas9 for example. If the driving mechanism(how sideeffects happen) is stated hypoxic tissue injury then well…

“Yes. One possibility is that the chromatin surrounding particular genes is in a fragile state after 1st exposure. E.g. there may be a high degree of DNA methylation but not enough to shut down gene expression totally. Upon re-exposure, the chromatin becomes more severely altered.
It’s possible. But even without DNA double-strand breaks there may be hypermethylation of the promoter regions of 5α-reductases, for example (in PFS). But not necessarily enough to shut down transcription. Upon re/cross exposure there may be further DNA hypermethylation.”

“There may even be additional layers of epigenetic control affected, that were not, or only mildly, affected on 1st exposure, such as histone deacetylation, further compacting the chromatin and shutting down gene expression of 5-ARs etc.”

“For PFS, the hypothetical sequence would be something like this: inhibition of 5-alpha reductase protein by finasteride leads to decreased transcription of the 5-AR gene. If chronic, over time the transcription factors that have altered transcription of the 5-AR promoter region…”

…will attract DNA methylases (e.g. DNMT3A) to the same promoter regions and induce de novo DNA methylation at that locus, thereby silencing transcription of the 5-AR gene. This process could continue with histone deacetylation etc."

From Antonie Csoka phd Twitter account

Direct link to the Twitter discussion in question:


There’s no elaboration as to if or how such changes might be reversible, should they occur.

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Of course that’s the biggest concern

Reversible or not
Or even treatable