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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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.
@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?
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?
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.
@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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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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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 μM, 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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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.
I promise you I’ll come back to this thread and post the publications I found on finasteride being a non-competitive inhibitor you have my word on that @arkaeik where did you get your info that finasteride was a non-competitor if you can please post as I don’t have a copy and paste option on this xbox. Honestly I wouldn’t trust any info that comes from the FDA as they are just fed what Merck tells them.
What if it did bind to the receptor sites irreversibly disabling them? I couldn’t find info that the body regenerates new receptors. There really isn’t information out there about the receptors and finasteride- this is just my hypothesis about the receptor sites not absolute fact but that’s why I’m reaching out to guys for help and to find answers.
I get that u think this, but i don’t think this is the case. As I said, I took SSRI and have the exact same persisting symptoms, without SSRI being an irreversible ihibitor. I think gene alterations is a way more plausible explanation for the persistance of symptoms.
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Every drug has different mechanisms although the sides are correlated. The Italian study had suggestered there was an abnormality at the AR level so this would go hand in hand with what I was saying about finasteride bonding to the receptor sites mutating them. This would also explain why people are having success with tribulus and l-carnetine which both resensitive the androgen receptors so that we can actually feel testosterone and DHT working. The solution to this madness might be finding a way to activate the androgen receptors or create new ones
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@Blueryan123 , the following should abolish any of your doubts about the recycling of AR:
The life cycle of AR is followed in the above article, from transcription of AR mRNA, to degradation by proteosomes. Degradation of misfolded/denatured proteins is also touched-upon. There are also estimated half-lives of AR provided that are hours, not days, months, or years.
Chawnshang Chang is one of the world’s leading androgen receptor researchers. He might even be considered the father of AR research, since he was the first to isolate and clone human AR. So, this is coming from a true authority on the matter.
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Why was @blueryan123 banned?? Really worried about the guy we should at least give him another chance on the forum.
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Your theory, thought logic and mindset is ahead of the curve. Anyone that has an issue with any of the thoughts you are proposing here is foolish.
I break down your thoughts as following:
Is Finasteride effecting the enzyme? And if so in a reversible or irreversible way?
Is finasteride effecting the receptors? And if so in a reversible or irreversible way?
Also another thing that should be seriously considered is despite the majority of information available indicating finasteride being a competitive inhibitor, is there another way it acts in a inreversible way?
These questions should be discussed in much greater detail. For now what I can add is that I have taken a drug called Mifepristone several times since 2017. It’s the female abortion drug which blocks progesterone receptors starving the fetus.
Mifepristone also blocks cortisol receptors and other receptors. It almost cured me in 2017 after a three day 50mg cycle of it. It cured me in the “snap back”. Meaning in the weeks following coming off of it. Mifepristone acts as an Antagonist binding to receptors as you stated “blocking them”. What’s going to happen when you block your receptors is that they are going to up regulate their sensitivity level in an attempt to make “their hormone” still be able to react with them them despite being blocked. Now if your receptors are down regulated this could be a possible fix because you would be up regulating down regulated receptors
I’m on day three of a 200 mg cycle of mifepristone currently. I will report my results in the up coming weeks
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Finasteride shares significant structural similarity with testosterone and DHT. It is thus possible that finasteride may act as a ligand to the androgen receptor (AR) in addition to its role as a 5α-reductase inhibitor. … Peroxiredoxin-1 (Prx1) is a novel endogenous modulator of AR binding to DHT.
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Interesting…
I’m not sure why he was proposing that Fin permanently blocks AR’s? By what mechanism? I guess in order to really know if what you posted abolishes any doubts about how he is saying fin permanently blocks AR’s we would need to know what his proposed mechanism is of how Fin is doing this ? Either way we have seen no evidence that Fin does this.
Initially though he was talking about the enzyme and if Fin works as a reversible or nonreversible inhibitor of the enzyme. And I think he has a point about this. I do remember reading Fin is a Nonreversible inhibitor years back. Now (like he was saying) those sources are just gone or at least harder to find…
Instead now everything says Fin is a competitive inhibitor which suggests it’s reversible. So I find this suspicious as well. Also if Fin is a competitor inhibitor it may still be acting in a nonreversible way. I think what it’s doing to the substrate should be looked at in more detail. Here:
http://cbm.msoe.edu/crest/posters/2015CUWSP/15finasteride.html](http://cbm.msoe.edu/crest/posters/2015CUWSP/15finasteride.html)
“Mechanism-based inactivation of 5α-reductase type 2 by finasteride showing a hydride reaction occurring between finasteride and NADPH that results in a covalent bond between finasteride and the cofactor. [R = -C(=O)-NH2; PADPR = 2’-phosphoadenosine-5’’-diphosphoribose; A-H = TYR58.7]”
We should look into this in more detail? What does this mean exactly? Covalent bond is permanent correct?
Also this:
“Although it is accepted as an alternate substrate and is ultimately reduced to dihydrofinasteride, this proceeds through an enzyme-bound NADP−dihydrofinasteride adduct”
“the binding of NADPHto the enzyme followed by the substrate”
Maybe you guys should try to get tested to see if you have still have dihydrofinasteride in your blood. I did not take fin so this is not an avenue for me to take.
Any updates on mifepristone?
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