Could this be the real cause of PFS

General Discussion
#1

This is incredibly important to all of us and I seen this mentioned on this platform before with the conversation going absolutely nowhere. So here goes: Is finasteride a reversible inhibitor or a irreversible suicide inhibitor? If everyone could please chip in here as this for me is the biggest question that needs answered on this forum.

My personal belief although it may or may not be true is that it is an irreversible inhibitor of 5alpha reductase that permanently alters the receptor sites so that they can no longer be activated this is what a suicide inhibitor will do. This could explain why those who are showing normal DHT levels but show all the symptoms of a deficiency because the hormone isn’t being activated by the receptor sites otherwise it’s just circulating in the blood doing nothing. These are just my opinions and aren’t based on facts but I have come to my own conclusion that this “may” be the cause of this syndrome and everything else is just a side effect.

Please everyone chip in and let me hear your thoughts

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Suppressed 3a-hydroxysteroid may be the cause?
#2

Finasteride is an irreversible inhibitor, it inhibits the conversion of testosterone to DHT. However the enzyme sites are regenerated regularly so this doesn’t explain why PFS happens. Also, as you mentioned, people with normal DHT levels still have PFS.

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#3

How do we know that enzymes sites are being regenerated from what I read they are often reused is this not correct? I can tell my DHT levels haven’t returned 8 months later from the total dryness of my entire skin so it makes very little as to why finasteride would still inhibit the DHT. The irreversible theory is my only guess as to why I’m not improving in fact I’ve got worse. Doesn’t finasteride denature the androgen receptors

#4

20 posts were split to a new topic: Discussion about estrogenic symptoms

Discussion about estrogenic symptoms
#5

If lack of DHT were the cause then taking DHT orally, or applying it to the genitals, would give great improvement. But most people report that it doesn’t work at all.

#6

I made that point already I believe we still convert DHT but it can’t be activated and my theory is that finasteride has irrevesibly bindind to the androgen receptors denaturing them so they can’t activate the proper mechanisms anymore. You never answered my question how do we know that the enzymes rejuvenate themselves? If you have any links that clears that up please post.

#12

I understand in the absence of DHT estrogen becomes dominate because DHT cancels estrogen out and is no longer activating properly that much we understand. The question remains why is DHT not activating? some have suggested it is down regulated but why are DHT levels still normal in blood tests. I had an instant bad reaction to finasteride so I don’t think it has anything to do with DHT flooding back into the system causing down regulation. I think once it binds to the enzymes and receptor sites that it permanently shuts them off and stops them from activating triggering a cascade of events in the body causing neuroinflammation, gut problems, muscle loss etc basically disrupts homeostasis. I noticed even women have oily skin and sweat to keep the skin moisturised so we know they have some amounts of DHT in their systems. I think a large portion of our androgens receptors have been permanently denatured by finasteride!

#13

Loss of muscle from the back which acts as support I lost all my muscle in the back and currently have severe back pain since using finasteride.

#14

Because proteins, including most enzymes, eventually get degraded. This also applies to receptors.

#15

So the body is constantly producing new receptors and enzymes why haven’t I seen one study that proves what you’re saying? Can you post some form of scientific literature that proves this please

#16

Once formed, proteins only exist for a certain period and are then degraded and recycled by the cell’s machinery through the process of protein turnover.

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#17

Hey if you check out receptor on wikipedia this is what it reads:

Antagonist bind to receptors but do not activate them. This results in a receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (reversible) and compete with the atagonist for the receptor, or they can be irreversible antagonists (Finasteride; I have included this reference to finasteride based on my own research that it is an irreversible inhibitor which is my own opinion) that form covolant bonds with the receptor and completely blocks it. The effects of irreversible antagonism can only be reversed by the synthesis of new receptors.

Enzymes do renew themselves but were is the data to say that the body makes new receptors? I could be wrong but I strongly believe they’re still being inhibited by finasteride that’s stopping the androgen receptors from activating at the sites. Finasteride may have mutated them so the substrate no longer recognises the sites (The keys no longer fit the locks) and so both testosterone and DHT can’t do their Jobs.

This is my theory and doesn’t represent facts backed by the scientific community only myself but I strongly believe this is what is happening to all of us.

#19

@awor @Dubya_B @AaronF @Mark2012
@holyhead @Invictus @Andrew35 @arkaeik @5-alpha
@AnhedonicApe

I’m sorry to bother you guys but this has been driving me crazy for weeks. Could you’s please chip in and let me know what you think about my theory on this. Is there a possibility this is what’s happening?

#20

Well the link I posted says proteins only exist for a limited amount of time. Why wouldn’t this include receptors? Also where did you get the idea that finasteride can bind to AR?

#21

My 2 cents is to repeat what @arkaeik posted about about protein turnover.:

The formation of the covalent bond between fin and 5-ar appears to be due to the enzymatic activity, so it shouldn’t have the same effect on the AR, even if it does have some binding affinity for the receptor.

#22

@Blueryan123 Hey, welcome to the forum! I like the way you are thinking, I feel the same way often times on this forum. It often feels like we need to start at first principles and then follow the path of Finasteride as it enters our body all the way to it creating our syndrome, each step of the way. At each step we use scientific literature and evidence to prove and disprove theories - and cancel each theory out as we test each one. It often feels like the answer is so simple, like the drug has just completely destroyed the bodies ability to make the 5AR enzyme in the right way, or that the receptors have just been destroyed to the sudden drop and rise of DHT etc…

For what it’s worth, from my understanding (please correct if I’m wrong here - because woah), Finasteride doesn’t affect the androgen receptor directly. It only affects the 5AR enzyme. The affect of this enzyme causes DHT, as well as a host of Neurotransmitters (Allopregenenalone Allo etc) to be completely shut off, or drastically reduced to minuscule levels. It is the reduction of these DHT and neurosteroid levels that causes the both neural and androgen receptors to be affected. How they are affected is still anyone’s guess. Some assume they are upregulated (for which we have a Melcangi study showing this - but I’m not ready to put all our money on this one study of penile tissue biopsies), others assume the receptors become down-regulated. The popular theory right now is that the receptors have an epigenetic switch that turns on when there is such a drastic reduction of DHT and neurosteroids, shutting them off entirely, and for good. This is what is (hopefully) being researched in the infamous Baylor study, which apparently is coming out any day now, and has been for the last 5 years. The above theories don’t include the host of other theories that others have had, particularly the affect PFS has on the gut - and the host of issues that could be getting caused there, or how much of this is simply in the mind, or if this is all just a really acute issue of estrogen dominance and its just a matter of resetting our hormones.

I really do wish people on this forum would understand that theorizing is great, and it’s the only tool we have in our current situation - but nobody cares about your ‘opinion’ on any of this unless it is backed by actual evidence. It’s so exhausting reading on here everyday some user saying “It’s my opinion that PFS is gut based etc” or “I don’t have to present data, this is just my opinion”… That’s great, but lets please make an honest attempt at doing some honest scientific work here (we’re not scientists, but we have no other option than to use scientific method). We need to come to the forum with a very well researched theory, that presents data to show how you’ve arrived at this conclusion.

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#23

I don’t understand why merck and co would fabricate a lie about finasteride being a competitive inhibitor then from what they presented to the FDA as opposed to what I had found in different publications online with it being a non-competitive inhibitor. I looked into every detail they provided to the FDA and thought something was out of place here how could a “safe” drug be crippling so many men out there what is the missing link that they aren’t telling us here and why is this “small” detail so important.

I think finasteride is blocking the receptor sites which is why some are having success with L-carnitine and Tribulus as both increase androgen sensitivity and number of androgen receptor sites as does resistance training.

I read that study and thought it was very interesting and I believe what causes the epignetic change is the androgen being hijacked by finasteride, I know agirl who had epignetic changes from drinking out of plastic bottles.

My biggest question is why aren’t all men experiencing symptoms perhaps their livers excreted the drug better than others and with us it caused hypertoxicity and an immune mediated attack from the sudden inhibtion of hormones.

Everything I say is based on conjecture and is soley my own opinion and I don’t base anything on facts*****

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#24

Thanks for your input @Dubya_B @arkaeik @Scott.H I appreciate your responses.

#34

I’m still confused. I’m not understanding where the information online about finasteride being a non-competitive inhibitor is coming from. I’m curious about this because I thought it might be an issue of semantics, with it possibly being described as a non-competitive inhibitor of the AR by reducing DHT.

I searched “finasteride non-competitive” on Scholar and Startpage searches and found nothing.

When searching for information about finasteride possibly binding to AR, the first thing that came up was a PDF published by the FDA stating that it had no affinity for the AR.

There was one study that described a possible competitive inhibition at the AR:

A primary mode of action of dutasteride and finasteride in blocking the AR signal can be attributed to competitive inhibition of DHT binding to AR. Both drugs are structural analogs of DHT, although dutasteride has a bulkier side chain substitution at the C17 position than finasteride [29]. This chemical feature may account for the greater advantage of dutasteride as a DHT competitor. The IC50 of dutasteride and finasteride is ~1.5 and 3.8 ÎźM, respectively, when R1881 (a synthetic androgen) is used as the ligand [30]. The stronger inhibitory effect of dutasteride also may be due to its higher bioavailability. In men, the circulating half-life of finasteride is 6-8 h, which is considerably shorter than the half-life of 3 days or more for dutasteride [31]. The finding suggests that dutasteride is metabolized slower systematically than finasteride. The prostate cancer cell lines used in this study also may have a low capacity for metabolizing dutasteride. In comparison to finasteride, more dutasteride may be retained intracellularly for a given period of time.

DHT binding to AR is known to be modulated by chaperone proteins, such as Prx1, Hsp90 and Hsp27 [32-34]. In a previous study, we found that lowering the level of Prx1 in prostate cancer cells by gene knockdown decreased substantially the affinity of DHT-AR interaction [32]. Cells with a poor source of these chaperone proteins may be more susceptible to dutasteride or finasteride because DHT can be displaced more easily from the AR. In addition to AR chaperones, post-translational modification of AR also may affect responsiveness to finasteride or dutasteride. At least 5 different post-translational modifications have been described, which include phosphorylation, acetylation, methylation, sumoylation and ubiquitination [35]. Little is known about the relationship between ligand binding and AR modifications. Different prostate cancer cell types may have different capacity and ways to modify AR. These changes could affect responsiveness to finasteride or dutasteride inhibition of AR activity.

Again though, the mechanism of the covalent binding of fin to 5-ar is due to the enzymatic activity according to the study I linked in my last post. This wouldn’t occur with a fin-AR interaction. It would act as a reversible competitive inhibitor. Even if there were covalent bonds formed with AR, proteosomal degradation of the junk protein and replacement would occur as per the link @arkaeik posted.

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#36

A bit off-topic, so I will not repeat it again in this thread, but I don’t understand why the hypothetical silencing of the AR signal, which I believe is being tested in the Baylor study, is so unpopular?

Especially considering the evidence provided by the Di Loreto study showing overexpression and abnormal expression of AR. That study was pretty straight-forward. They took cells from the same area of PFS and controls and performed a simple immunohistostaining procedure (antibody-based stain specific for a certain protein) and noticed a difference under the microscope.