Inhibiting 5ap at the molecular level and trying to describe what happens next

[Resurection]

Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride - PubMed

Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride as SRD5α2 inhibitors are widely...

pubmed.ncbi.nlm.nih.gov

It seemed interesting to me, even if it's not new information.

They found a way and examined in minute detail how the 5ar enzyme is structured and how finasteride acts on it.

As I understood from the article, two important amino acids work in the enzyme's active site, E57 (glutamate) and Y91 (tyrosine).

1. Tyrosine (y91) - captures the testosterone molecule and holds it.
2. Glutamate (e57) - takes a hydrogen atom from the testosterone molecule, preparing a "blank," so to speak. This allows it to accept a charge from NADPH, and the process of conversion to dihydrotestosterone occurs. NADPH, losing its charge, becomes NADP and leaves for recycling and other enzymes.

This is the normal process.

Finasteride, having a structure similar to testosterone (progesterone), interferes with this process. Tyrosine captures it, and glutamate takes NADPH but cannot process it into NADP. Thus, the output is NADP-dihydrotestosterone. This NADP-DGT gets stuck in the active site, and the enzyme stops. Now NADPH and finasteride are bound, and NADPH can no longer enter the enzyme.

As far as I understand, this bond is permanent, it cannot be broken or corrected. The enzyme is now spoiled.

In theory, the body should find, mark, and dispose of such an enzyme using protein recovery systems.

I'll try to list them and describe them briefly.

1. Cellular protein repair systems. (fix minor protein damage)
2. Chaperones. (control amino acids that carry out protein assembly and prevent amino acids from sticking together)
3. Ubiquitin-proteasome system (UPS). (system for disposing of damaged proteins)
4. Autophagy. (large-scale recycling system)

For example, the ubiquitin-proteasome system (UPS),

Ubiquitin places a mark on the protein, and the proteasome breaks it down. Ubiquitin creates a thioester bond with the active site of E1 and E2 enzymes, and this center is a cysteine residue. If the cysteine is oxidized, the magic won't happen, the enzyme won't be marked and disposed of.

Cysteine is highly sensitive to oxidative stress, so oxidative stress can lead to its oxidation into sulfate forms and problems with ubiquitin's function.

The proteasome has A and B subunits. The entire enzymatic reaction occurs in the B subunits. Their active site also contains a cysteine residue, which, as already mentioned, depends on the redox balance.

All these systems are highly dependent on ATP and pH.


#.
In the end (I assume), the cell will accumulate protein debris and synthesize a new enzyme, if it is still capable of normal synthesis – which is also questionable. The accumulation of debris will clog the cell and create even more oxidation within it, considering that the process of such mass assembly and disposal is very energy-intensive and oxidative.

Likely, the cell will be clogged precisely where this protein was destroyed, i.e., in the case of finasteride, that's the prostate, hair follicles, penis, intestinal mucosa, liver, etc. And hypothetically, it would affect precisely these systems.

Also, the UPS might not even mark the enzyme, and it won't be destroyed at all if there are problems with ubiquitination. Or it might assemble these proteins with errors if there are folding problems (chaperones).

Actually, it's difficult to predict the exact outcome of such a disruption – what will happen after discontinuation, what happens during intake, etc. There are many variations, but this could explain the illogical nature of how people experience disorders differently.


#.
The idea is that due to pre-existing problems and an impaired redox balance, the body cannot properly dispose of or synthesize new enzymes. That is, there is a failure in these systems, particularly, I assume, the UPS and autophagy.

In such an environment, we take finasteride, and this leads to the consequences that each of us now has. This might also be why fasting (autophagy) helps many.

1. This would explain my case and the cases of others who got PFS, PSSD, and post-aromatase inhibitor syndrome from 1 tablet. Because there's no logic – you take 1 tablet and get a crash at the moment of intake. Not enough time has passed for anything to upregulate, downregulate, or change epigenetically. Heavy metal problems don't fit here either. They can't accumulate and become so toxic in 5 minutes. I've checked repeatedly, receptor regulation happens on average in 12-24 hours. My crash happened within 5-10 minutes of taking it, i.e., as soon as the drug became active. And this crash remained, in the same state.

2. If finasteride accumulates in the liver, then it should, in theory, act as an inhibitor (if, while in the liver, it still acts as finasteride). Then there wouldn't be crashes after discontinuation, you would just be stuck, and it would continue to block your 5ar, accumulating in the liver. I assume the symptoms would be the same as from taking the drug, but for many, re-taking 5ar inhibitors relieves almost all symptoms, which seems illogical to me.

3. If finasteride systemically disrupts NADPH metabolism and that's the issue, then the symptoms should be identical for everyone, or at least, not tied to the inhibited enzyme. But we see how, for people, everything is linked to the drug they took. For example, for those who took SSRIs, everything is tied to serotonin. For those who took finasteride, to 5ar. For post-aromatase, to estrogen. I think the same thing would happen to those in a similar state who take drugs similar to finasteride, for example, irreversible MAO inhibitors, acetylcholinesterase inhibitors, etc.

If we take NADPH as the key link, then, for example, SERT doesn't use NADPH for its activity, it needs ionic gradients (sodium-potassium channels).

4. This could explain why all these syndromes are related to enzymes (proteins) and the liver (antioxidants).

5. This could explain why some, whose crash is milder, recover over time. The body, over time, cleans up the junk proteins, apparently still having enough resources.


#.
Now, I want to talk a bit about 5-alpha reductase. It's well known that it is divided into types. Finasteride affects 5ar type 1 and type 2.

Type 1 is the most interesting. Unlike type 2, it is very widespread in the intestines, particularly in some bacteria and in the cells of the mucous membrane (enterocytes). 5ar type 1 converts 5B-CDCA (chenodeoxycholic acid) into 5A-CDCA (allochenodeoxycholic acid). Then, it can be converted into allolithocholic acid by bacteria. This is the process of converting primary bile acid into secondary.

It is the primary bile acid (chenodeoxycholic acid) that is the toxic form, it can damage cells, and 5ar type 1 removes it.

Why is this needed, Besides the obvious, where bile acids play a role in fat metabolism, 5A-DCA powerfully removes bacterial biofilms, which promotes the killing of the bacteria themselves in the small intestine and SIBO as a result. 5A-DCA itself is already a secondary bile acid, it has a hydrophobic structure, which allows it to effectively integrate into bacterial membranes.

Without this, there will be SIBO growth, malabsorption, impaired absorption and systemic inflammation, as well as all those interesting autoimmune symptoms that we have.

Hence, iNOS is constantly elevated because you have a bacterial load, but it can't kill anything there, and you have gum loss, collagen loss, mucus loss (dryness), increased ROS, lots of histamine, problems with serotonin, and the list of these symptoms goes on.

TUDCA, which helps many, combines 2 things. Taurine and UDCA (a secondary bile acid). Essentially, it involves attaching a sulfuric amino acid to the bile acid core, resulting in conjugation. Therefore, if people want to take bile, they should take not ox bile, but bear bile, as bear bile contains TUDCA. But this doesn't cure people, it mimics what the body should do on its own, with the help of 5ar. I even suspect it might inhibit 5ar.

Taurine itself, as I already wrote somewhere else in another topic, attaches at the final stage of bile acid conjugation. Taurine needs sulfur, it needs cysteine and methionine. Methionine acts as a sulfur donor, where further homocysteine and the CBS pathway (cysteine) then go into taurine. Briefly, without methylation, there will be almost no taurine and no normal bile. Also, taurine is an agonist of GABA A, α4βδ subunits, the same subunits targeted by allopregnanolone.


#.
Of all the theories proposed earlier, epigenetics is probably the only logical explanation. But how could epigenetics happen in 5-10 minutes in my case, As mentioned earlier, I got a crash from the very action of the drug, not as a result of its long-term use.

If we take the theories discussed on this site. I don't fully understand how 1 enzyme (5ar), by binding 1 molecule (NADPH), can systemically shift an entire ocean of electrons (NADPH), Even if there are many enzymes, it's still small compared to the total NADPH pool. In my opinion, it's like approaching a river and scooping up a bucket of water.

Maybe I'm wrong, of course, and because NADPH isn't recycled into NADP, the body has to produce it all over again, reconfigure pathways, enzymes, etc. But again, why should this be linked specifically to androgens in the case of finasteride, or, for example, serotonin in the case of PSSD, If it were systemic, the symptoms should be blurred, like in diabetics.

In my opinion, it's a self-sustaining process. Pre-existing problems , Oxidative stress - decreased ATP - Problem with UPS, autophagy - Finasteride - Creation of debris - Worsening oxidative stress - Inflammation - Cell signal to increase cytokines - Increase in nfkb, tnfa, cox, etc. - Systemic inflammation - Massive loss and halt of ATP production. And so on in a circle. As we've seen, for many with serious crashes, it worsens over time, it becomes harder for them to recover.


#.
As already mentioned, UPS is highly dependent on ATP, with problems in the mitochondria (respiratory chain, oxidative phosphorylation, etc.), there simply won't be enough energy for synthesis or its activity. For these systems to work, zinc, magnesium, selenium, B vitamins are needed. Also, all amino acids are needed, especially Lysine.

There's another point. NRF2 - the main regulator of antioxidants and the UPS. In particular, it is activated when there is a lot of ROS in the cell. It also regulates the expression of s20 and s19 genes (proteasomes) and E3 ubiquitin ligases (ubiquitins). Nrf2 works on zinc fingers and is associated with AR. There was a study (but unfortunately I lost the link), where AR regulated the expression of some UPS components, possibly due to overlap with zinc fingers. Therefore, perhaps we have a connection with this also at the level of the AR receptor.


#.
Now, if we look at the average person with PFS, we see that they have almost no methylation. Homocysteine is high, folates are low, B12 is often low too. There is no glutathione production, and in this state, they try to take selenium. Their cysteine is constantly oxidized into cystine and further into sulfate forms. As a result, half of this cysteine doesn't even reach glutathione, and what does reach isn't recycled but is constantly created from scratch due to NADPH deficiency. Now, if we start spinning their folate cycle, no shifts occur, or they get side effects because NADPH is needed in almost all reactions, and it's maximally reduced, which likely causes the g6pd enzyme to be highly activated, diverting glucose to itself, and not to pyruvate and ATP synthesis. This constantly creates ribose as the end product of metabolism.

Hence, I think, the problems with acetyl-CoA in people (although this is a debatable point, perhaps the body has enough from proteins and fats).

Insulin is probably constantly active, and possibly, against this background, its receptor is downregulated, preventing sugar from entering the cell, and all this wastes potassium, wastes B vitamins.

Besides this, all this oxidative stress will require antioxidants, and that's copper, zinc, manganese, iron, chromium, all B vitamins. And at the same time, it will require ROS to deal with pathogens and maintain the immune system. In connection with this, NADPH Oxidase will be elevated and will consume NADPH, reducing it even further. Probably, this is why, in many cases, people's hormones are low, since steroidogenesis requires a lot of ATP and NADPH.

Also, there will likely be competition for NAD. Low NADPH will require NADP, NADP in turn will require NAD and ATP, this can lead to a decrease in NADH and ATP synthesis as a consequence. Probably, the body will greatly increase the activity of NADK and intensively spend niacin and magnesium, which is also a blow to ATP.

And all this, with a severely damaged GI tract that absorbs almost nothing properly. This person simply gets stuck in all this, it's no wonder the body resorts to epigenetics.

To avoid misunderstanding, above, I tried to summarize and describe the overall picture of a person with PFS. People have crashes of different scales – some simpler, some more complex. Again, everyone has different metabolism and oxidation rates, and it's simply impossible to describe everyone at once. Probably, the picture will differ for some people.

If I had to roughly generalize, I would say that the loss of ATP and the body's inability to produce it is a key point for all systems. But the loss of ATP is also a consequence.


#.
Overall, I agree with the direction of this forum, that it is necessary to support redox systems, this, in my view, is the main thing. The problem is only that your GI tract won't allow you to do this directly, especially for those with severe disorders, who, for example, used finasteride in higher doses or repeatedly after a crash. It is necessary for the body to absorb everything you give it and accumulate it. We have a bile problem, which leads to SIBO. SIBO leads to malabsorption, problems with absorption and breakdown, problems with inflammation and oxidation, decreased antioxidants, and ultimately, deficiencies. This is difficult to mimic with supplements, here you need butyrate for the mucous membranes and gene regulation, you need acid, you need to reduce the bacterial load and activate bile flow (sphincter of Oddi), as well as its proper conjugation and fluidity. Without a powerful flow, bacteria in the small intestine can remain. They die not only from the mere presence of bile but also from its composition, thickness, and, importantly, the force of the flow. And if there is no normal conversion into secondary bile acids, it can even become toxic.


#.
It would be legitimate to ask why HCG treated some, or, for example, taking DHT, I assume you are forcing the activation of all these pathways. HCG, as an analogue of LH, will force the synthesis of cholesterol and activate steroidogenesis. For 1 molecule of cholesterol, 2 molecules of NADPH are needed, not to mention steroidogenesis itself. In general, this will increase its production and lead to a cascade of dependent reactions. For example, massive ATP production will be needed, I think the body will take everything it has for this process. Thus, I assume the cell receives resources and cleans up all this protein-oxidative debris.

Perhaps, if you strongly downregulate androgen, estrogen, and, for example, GABA receptors, this would also force the body to produce more hormones and activate all these pathways. But this is just an assumption, it's unlikely anyone would do that.

I already described one case with a guy on this forum. He walked in the sun, 10 km a day, and eventually recovered. Previously, I thought it was about D3 and activation of cyp3a4, which removed the drug from the liver and he recovered, but I think there's a different mechanism here. D3 induces StaR, like HCG, and increases LH, this (I assume) forces the body to produce hormones from cholesterol, and here the principle is similar to HCG, in my opinion. There's no point in HCG upregulating AR, in people with PFS, these receptors are already elevated.

Of course, I might be wrong, and the guy was cured by the walking itself, not the sun.


#.
Let me summarize.

Why impaired protein metabolism, Because it can explain all similar syndromes at once, which an imbalance of NADPH/NADP does not explain. SSRIs, for example, do not bind NADPH. And still, I don't rule out that possibility, but then it must be about a local disruption of electrons, where we inhibited 5ar.

I don't know if this can be called a theory, it's more just my thoughts. I could be wrong. This can be argued with, criticized, supplemented, and developed, I generally don't claim to know the truth.

In any case, I think it will be useful to understand how finasteride does this and try to understand what happens after its discontinuation or at the moment of intake.

 

[zancek0]

Thank you, this is a very well written and argued post

 

[merebalacy]

Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride - PubMed

Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride as SRD5α2 inhibitors are widely...

pubmed.ncbi.nlm.nih.gov

It seemed interesting to me, even if it's not new information.

They found a way and examined in minute detail how the 5ar enzyme is structured and how finasteride acts on it.

As I understood from the article, two important amino acids work in the enzyme's active site, E57 (glutamate) and Y91 (tyrosine).

1. Tyrosine (y91) - captures the testosterone molecule and holds it.
2. Glutamate (e57) - takes a hydrogen atom from the testosterone molecule, preparing a "blank," so to speak. This allows it to accept a charge from NADPH, and the process of conversion to dihydrotestosterone occurs. NADPH, losing its charge, becomes NADP and leaves for recycling and other enzymes.

This is the normal process.

Finasteride, having a structure similar to testosterone (progesterone), interferes with this process. Tyrosine captures it, and glutamate takes NADPH but cannot process it into NADP. Thus, the output is NADP-dihydrotestosterone. This NADP-DGT gets stuck in the active site, and the enzyme stops. Now NADPH and finasteride are bound, and NADPH can no longer enter the enzyme.

As far as I understand, this bond is permanent, it cannot be broken or corrected. The enzyme is now spoiled.

In theory, the body should find, mark, and dispose of such an enzyme using protein recovery systems.

I'll try to list them and describe them briefly.

1. Cellular protein repair systems. (fix minor protein damage)
2. Chaperones. (control amino acids that carry out protein assembly and prevent amino acids from sticking together)
3. Ubiquitin-proteasome system (UPS). (system for disposing of damaged proteins)
4. Autophagy. (large-scale recycling system)

For example, the ubiquitin-proteasome system (UPS),

Ubiquitin places a mark on the protein, and the proteasome breaks it down. Ubiquitin creates a thioester bond with the active site of E1 and E2 enzymes, and this center is a cysteine residue. If the cysteine is oxidized, the magic won't happen, the enzyme won't be marked and disposed of.

Cysteine is highly sensitive to oxidative stress, so oxidative stress can lead to its oxidation into sulfate forms and problems with ubiquitin's function.

The proteasome has A and B subunits. The entire enzymatic reaction occurs in the B subunits. Their active site also contains a cysteine residue, which, as already mentioned, depends on the redox balance.

All these systems are highly dependent on ATP and pH.


#.
In the end (I assume), the cell will accumulate protein debris and synthesize a new enzyme, if it is still capable of normal synthesis – which is also questionable. The accumulation of debris will clog the cell and create even more oxidation within it, considering that the process of such mass assembly and disposal is very energy-intensive and oxidative.

Likely, the cell will be clogged precisely where this protein was destroyed, i.e., in the case of finasteride, that's the prostate, hair follicles, penis, intestinal mucosa, liver, etc. And hypothetically, it would affect precisely these systems.

Also, the UPS might not even mark the enzyme, and it won't be destroyed at all if there are problems with ubiquitination. Or it might assemble these proteins with errors if there are folding problems (chaperones).

Actually, it's difficult to predict the exact outcome of such a disruption – what will happen after discontinuation, what happens during intake, etc. There are many variations, but this could explain the illogical nature of how people experience disorders differently.


#.
The idea is that due to pre-existing problems and an impaired redox balance, the body cannot properly dispose of or synthesize new enzymes. That is, there is a failure in these systems, particularly, I assume, the UPS and autophagy.

In such an environment, we take finasteride, and this leads to the consequences that each of us now has. This might also be why fasting (autophagy) helps many.

1. This would explain my case and the cases of others who got PFS, PSSD, and post-aromatase inhibitor syndrome from 1 tablet. Because there's no logic – you take 1 tablet and get a crash at the moment of intake. Not enough time has passed for anything to upregulate, downregulate, or change epigenetically. Heavy metal problems don't fit here either. They can't accumulate and become so toxic in 5 minutes. I've checked repeatedly, receptor regulation happens on average in 12-24 hours. My crash happened within 5-10 minutes of taking it, i.e., as soon as the drug became active. And this crash remained, in the same state.

2. If finasteride accumulates in the liver, then it should, in theory, act as an inhibitor (if, while in the liver, it still acts as finasteride). Then there wouldn't be crashes after discontinuation, you would just be stuck, and it would continue to block your 5ar, accumulating in the liver. I assume the symptoms would be the same as from taking the drug, but for many, re-taking 5ar inhibitors relieves almost all symptoms, which seems illogical to me.

3. If finasteride systemically disrupts NADPH metabolism and that's the issue, then the symptoms should be identical for everyone, or at least, not tied to the inhibited enzyme. But we see how, for people, everything is linked to the drug they took. For example, for those who took SSRIs, everything is tied to serotonin. For those who took finasteride, to 5ar. For post-aromatase, to estrogen. I think the same thing would happen to those in a similar state who take drugs similar to finasteride, for example, irreversible MAO inhibitors, acetylcholinesterase inhibitors, etc.

If we take NADPH as the key link, then, for example, SERT doesn't use NADPH for its activity, it needs ionic gradients (sodium-potassium channels).

4. This could explain why all these syndromes are related to enzymes (proteins) and the liver (antioxidants).

5. This could explain why some, whose crash is milder, recover over time. The body, over time, cleans up the junk proteins, apparently still having enough resources.


#.
Now, I want to talk a bit about 5-alpha reductase. It's well known that it is divided into types. Finasteride affects 5ar type 1 and type 2.

Type 1 is the most interesting. Unlike type 2, it is very widespread in the intestines, particularly in some bacteria and in the cells of the mucous membrane (enterocytes). 5ar type 1 converts 5B-CDCA (chenodeoxycholic acid) into 5A-CDCA (allochenodeoxycholic acid). Then, it can be converted into allolithocholic acid by bacteria. This is the process of converting primary bile acid into secondary.

It is the primary bile acid (chenodeoxycholic acid) that is the toxic form, it can damage cells, and 5ar type 1 removes it.

Why is this needed, Besides the obvious, where bile acids play a role in fat metabolism, 5A-DCA powerfully removes bacterial biofilms, which promotes the killing of the bacteria themselves in the small intestine and SIBO as a result. 5A-DCA itself is already a secondary bile acid, it has a hydrophobic structure, which allows it to effectively integrate into bacterial membranes.

Without this, there will be SIBO growth, malabsorption, impaired absorption and systemic inflammation, as well as all those interesting autoimmune symptoms that we have.

Hence, iNOS is constantly elevated because you have a bacterial load, but it can't kill anything there, and you have gum loss, collagen loss, mucus loss (dryness), increased ROS, lots of histamine, problems with serotonin, and the list of these symptoms goes on.

TUDCA, which helps many, combines 2 things. Taurine and UDCA (a secondary bile acid). Essentially, it involves attaching a sulfuric amino acid to the bile acid core, resulting in conjugation. Therefore, if people want to take bile, they should take not ox bile, but bear bile, as bear bile contains TUDCA. But this doesn't cure people, it mimics what the body should do on its own, with the help of 5ar. I even suspect it might inhibit 5ar.

Taurine itself, as I already wrote somewhere else in another topic, attaches at the final stage of bile acid conjugation. Taurine needs sulfur, it needs cysteine and methionine. Methionine acts as a sulfur donor, where further homocysteine and the CBS pathway (cysteine) then go into taurine. Briefly, without methylation, there will be almost no taurine and no normal bile. Also, taurine is an agonist of GABA A, α4βδ subunits, the same subunits targeted by allopregnanolone.


#.
Of all the theories proposed earlier, epigenetics is probably the only logical explanation. But how could epigenetics happen in 5-10 minutes in my case, As mentioned earlier, I got a crash from the very action of the drug, not as a result of its long-term use.

If we take the theories discussed on this site. I don't fully understand how 1 enzyme (5ar), by binding 1 molecule (NADPH), can systemically shift an entire ocean of electrons (NADPH), Even if there are many enzymes, it's still small compared to the total NADPH pool. In my opinion, it's like approaching a river and scooping up a bucket of water.

Maybe I'm wrong, of course, and because NADPH isn't recycled into NADP, the body has to produce it all over again, reconfigure pathways, enzymes, etc. But again, why should this be linked specifically to androgens in the case of finasteride, or, for example, serotonin in the case of PSSD, If it were systemic, the symptoms should be blurred, like in diabetics.

In my opinion, it's a self-sustaining process. Pre-existing problems , Oxidative stress - decreased ATP - Problem with UPS, autophagy - Finasteride - Creation of debris - Worsening oxidative stress - Inflammation - Cell signal to increase cytokines - Increase in nfkb, tnfa, cox, etc. - Systemic inflammation - Massive loss and halt of ATP production. And so on in a circle. As we've seen, for many with serious crashes, it worsens over time, it becomes harder for them to recover.


#.
As already mentioned, UPS is highly dependent on ATP, with problems in the mitochondria (respiratory chain, oxidative phosphorylation, etc.), there simply won't be enough energy for synthesis or its activity. For these systems to work, zinc, magnesium, selenium, B vitamins are needed. Also, all amino acids are needed, especially Lysine.

There's another point. NRF2 - the main regulator of antioxidants and the UPS. In particular, it is activated when there is a lot of ROS in the cell. It also regulates the expression of s20 and s19 genes (proteasomes) and E3 ubiquitin ligases (ubiquitins). Nrf2 works on zinc fingers and is associated with AR. There was a study (but unfortunately I lost the link), where AR regulated the expression of some UPS components, possibly due to overlap with zinc fingers. Therefore, perhaps we have a connection with this also at the level of the AR receptor.


#.
Now, if we look at the average person with PFS, we see that they have almost no methylation. Homocysteine is high, folates are low, B12 is often low too. There is no glutathione production, and in this state, they try to take selenium. Their cysteine is constantly oxidized into cystine and further into sulfate forms. As a result, half of this cysteine doesn't even reach glutathione, and what does reach isn't recycled but is constantly created from scratch due to NADPH deficiency. Now, if we start spinning their folate cycle, no shifts occur, or they get side effects because NADPH is needed in almost all reactions, and it's maximally reduced, which likely causes the g6pd enzyme to be highly activated, diverting glucose to itself, and not to pyruvate and ATP synthesis. This constantly creates ribose as the end product of metabolism.

Hence, I think, the problems with acetyl-CoA in people (although this is a debatable point, perhaps the body has enough from proteins and fats).

Insulin is probably constantly active, and possibly, against this background, its receptor is downregulated, preventing sugar from entering the cell, and all this wastes potassium, wastes B vitamins.

Besides this, all this oxidative stress will require antioxidants, and that's copper, zinc, manganese, iron, chromium, all B vitamins. And at the same time, it will require ROS to deal with pathogens and maintain the immune system. In connection with this, NADPH Oxidase will be elevated and will consume NADPH, reducing it even further. Probably, this is why, in many cases, people's hormones are low, since steroidogenesis requires a lot of ATP and NADPH.

Also, there will likely be competition for NAD. Low NADPH will require NADP, NADP in turn will require NAD and ATP, this can lead to a decrease in NADH and ATP synthesis as a consequence. Probably, the body will greatly increase the activity of NADK and intensively spend niacin and magnesium, which is also a blow to ATP.

And all this, with a severely damaged GI tract that absorbs almost nothing properly. This person simply gets stuck in all this, it's no wonder the body resorts to epigenetics.

To avoid misunderstanding, above, I tried to summarize and describe the overall picture of a person with PFS. People have crashes of different scales – some simpler, some more complex. Again, everyone has different metabolism and oxidation rates, and it's simply impossible to describe everyone at once. Probably, the picture will differ for some people.

If I had to roughly generalize, I would say that the loss of ATP and the body's inability to produce it is a key point for all systems. But the loss of ATP is also a consequence.


#.
Overall, I agree with the direction of this forum, that it is necessary to support redox systems, this, in my view, is the main thing. The problem is only that your GI tract won't allow you to do this directly, especially for those with severe disorders, who, for example, used finasteride in higher doses or repeatedly after a crash. It is necessary for the body to absorb everything you give it and accumulate it. We have a bile problem, which leads to SIBO. SIBO leads to malabsorption, problems with absorption and breakdown, problems with inflammation and oxidation, decreased antioxidants, and ultimately, deficiencies. This is difficult to mimic with supplements, here you need butyrate for the mucous membranes and gene regulation, you need acid, you need to reduce the bacterial load and activate bile flow (sphincter of Oddi), as well as its proper conjugation and fluidity. Without a powerful flow, bacteria in the small intestine can remain. They die not only from the mere presence of bile but also from its composition, thickness, and, importantly, the force of the flow. And if there is no normal conversion into secondary bile acids, it can even become toxic.


#.
It would be legitimate to ask why HCG treated some, or, for example, taking DHT, I assume you are forcing the activation of all these pathways. HCG, as an analogue of LH, will force the synthesis of cholesterol and activate steroidogenesis. For 1 molecule of cholesterol, 2 molecules of NADPH are needed, not to mention steroidogenesis itself. In general, this will increase its production and lead to a cascade of dependent reactions. For example, massive ATP production will be needed, I think the body will take everything it has for this process. Thus, I assume the cell receives resources and cleans up all this protein-oxidative debris.

Perhaps, if you strongly downregulate androgen, estrogen, and, for example, GABA receptors, this would also force the body to produce more hormones and activate all these pathways. But this is just an assumption, it's unlikely anyone would do that.

I already described one case with a guy on this forum. He walked in the sun, 10 km a day, and eventually recovered. Previously, I thought it was about D3 and activation of cyp3a4, which removed the drug from the liver and he recovered, but I think there's a different mechanism here. D3 induces StaR, like HCG, and increases LH, this (I assume) forces the body to produce hormones from cholesterol, and here the principle is similar to HCG, in my opinion. There's no point in HCG upregulating AR, in people with PFS, these receptors are already elevated.

Of course, I might be wrong, and the guy was cured by the walking itself, not the sun.


#.
Let me summarize.

Why impaired protein metabolism, Because it can explain all similar syndromes at once, which an imbalance of NADPH/NADP does not explain. SSRIs, for example, do not bind NADPH. And still, I don't rule out that possibility, but then it must be about a local disruption of electrons, where we inhibited 5ar.

I don't know if this can be called a theory, it's more just my thoughts. I could be wrong. This can be argued with, criticized, supplemented, and developed, I generally don't claim to know the truth.

In any case, I think it will be useful to understand how finasteride does this and try to understand what happens after its discontinuation or at the moment of intake.

Great post bro

 

[TubZy]

Excellent write up. I think it effects each person to a different extent since you were sick/unbalanced prior to taking finasteride. If you have hair loss you have a metabolic imbalance/disorder whether it be glutathione wasting/poor recycling and body is pulling cysteine from the hair or your AR/GR were dysregulated. So depending on the persons current state if they take finasteride that can upset the imbalance NADPH/NADP in different ways being more severe than others. I remember I took fin twice. First time I took it for a few months and get sides and stopped and everything returned to normal including aggressive hairloss. A few months later I decided to give it another go and that is when I get sides while on and then quit and then boom PFS. So I think since I started the second time at a worse baseline the body basically could no longer regulate any longer and just shutdown.

I agree there are really three main options:

epigenetics (HDAC inhibitors etc)

Epigenetic changes from Finasteride.( Demethylation protocol and explanation of Demethylating ENZYMES)

@zadig777 @talkingant As we saw from the studies, fin might have caused the epigenetic changes. What it all means. There are 3 parts of the Androgen receptor . 1) the BINDING Part where the hormone BINDS to. ( usually people talk about this part) 2) then there is a zinc finger...

hackstas.is

Push the ATP/Krebs/Citric/Malic acid cycle via B vitamins/aminos/potassium and basically feed everything the body needs to comfortably push metabolism back online. This was pretty much my recovery of just pushing massive amounts of potassium and aminos.

Electrolyte Protocol for Improved Health

This program was posted in 2012 . And has not been changed since then pretty much. DETOX procedures are very important part of this program. You need to get all the drugs out of your system, for that you need to increase sulfation. LOOK AT DETOX PART. YOU HAVE TO TAKE THAT PART DAILY...

hackstas.is

Downregulate AR/GR receptors (DHT for AR, quercetin for GR, maybe Ozone for AR too? )

There are some additional recoveries. Once was pine pollen + potassium (downregulates AR and high doses of potassium downregulate GR) and the other was histidine + B2 which basically does similar action to HDAC inhibitors as histidine and B2 make up your body's natural demethylating enzymes.

Additionally histidine pushes glutathione and B2 recycles it.

Quercetin also recovered someone twice I believe at 3 grams a day taken once daily. It downregulates GR but also has strong HDACI properties. Maybe works in synergy.

 

[Resurection]

Excellent write up. I think it effects each person to a different extent since you were sick/unbalanced prior to taking finasteride. If you have hair loss you have a metabolic imbalance/disorder whether it be glutathione wasting/poor recycling and body is pulling cysteine from the hair or your AR/GR were dysregulated. So depending on the persons current state if they take finasteride that can upset the imbalance NADPH/NADP in different ways being more severe than others. I remember I took fin twice. First time I took it for a few months and get sides and stopped and everything returned to normal including aggressive hairloss. A few months later I decided to give it another go and that is when I get sides while on and then quit and then boom PFS. So I think since I started the second time at a worse baseline the body basically could no longer regulate any longer and just shutdown.

I agree there are really three main options:

epigenetics (HDAC inhibitors etc)

Epigenetic changes from Finasteride.( Demethylation protocol and explanation of Demethylating ENZYMES)

@zadig777 @talkingant As we saw from the studies, fin might have caused the epigenetic changes. What it all means. There are 3 parts of the Androgen receptor . 1) the BINDING Part where the hormone BINDS to. ( usually people talk about this part) 2) then there is a zinc finger...

hackstas.is

Push the ATP/Krebs/Citric/Malic acid cycle via B vitamins/aminos/potassium and basically feed everything the body needs to comfortably push metabolism back online. This was pretty much my recovery of just pushing massive amounts of potassium and aminos.

Electrolyte Protocol for Improved Health

This program was posted in 2012 . And has not been changed since then pretty much. DETOX procedures are very important part of this program. You need to get all the drugs out of your system, for that you need to increase sulfation. LOOK AT DETOX PART. YOU HAVE TO TAKE THAT PART DAILY...

hackstas.is

Downregulate AR/GR receptors (DHT for AR, quercetin for GR, maybe Ozone for AR too? )

There are some additional recoveries. Once was pine pollen + potassium (downregulates AR and high doses of potassium downregulate GR) and the other was histidine + B2 which basically does similar action to HDAC inhibitors as histidine and B2 make up your body's natural demethylating enzymes.

Additionally histidine pushes glutathione and B2 recycles it.

Quercetin also recovered someone twice I believe at 3 grams a day taken once daily. It downregulates GR but also has strong HDACI properties. Maybe works in synergy.

Yes, there is an initial disruption. In the first post, I tried to hypothesize what exactly is impaired in us and how it might happen. In principle, for those who are interested, we can discuss other pathways, using how finasteride works as a starting point.

I assume that by "regulation" you are talking about the regulation of receptor density? It's just that in PFS, it's necessary to demethylate the receptor. This is when demethylase enzymes remove methyl groups from the cytosine bases in the receptor gene itself. Density regulation (downregulation and upregulation) is essentially the regulation of the receptors themselves on the membrane.

Essentially, your two points can be combined into one.

In theory, testosterone should demethylate the AR, but for some reason, it doesn't cure people with PFS.

Demethylation actually activates the receptor gene and increases its density on the membrane. So, it seems that the impaired methylation status itself can alter the receptor's function at the gene level and cause, for example, hair loss in people.

I remember one case, long before I found myself in this boat, a guy was growing hair by increasing methylation. This was on some hair loss forum. It's certainly not a panacea for everyone, but it's an interesting case.

The stuff about histidine and B2 is interesting, thanks.

Regarding pine pollen, does pine pollen actually reduce AR? I thought it inhibits or does something to 5AR, which should, in theory, cause AR to rise. I'm still curious about its mechanism of action.

 

[TubZy]

Yes, there is an initial disruption. In the first post, I tried to hypothesize what exactly is impaired in us and how it might happen. In principle, for those who are interested, we can discuss other pathways, using how finasteride works as a starting point.

I assume that by "regulation" you are talking about the regulation of receptor density? It's just that in PFS, it's necessary to demethylate the receptor. This is when demethylase enzymes remove methyl groups from the cytosine bases in the receptor gene itself. Density regulation (downregulation and upregulation) is essentially the regulation of the receptors themselves on the membrane.

Essentially, your two points can be combined into one.

In theory, testosterone should demethylate the AR, but for some reason, it doesn't cure people with PFS.

Demethylation actually activates the receptor gene and increases its density on the membrane. So, it seems that the impaired methylation status itself can alter the receptor's function at the gene level and cause, for example, hair loss in people.

I remember one case, long before I found myself in this boat, a guy was growing hair by increasing methylation. This was on some hair loss forum. It's certainly not a panacea for everyone, but it's an interesting case.

The stuff about histidine and B2 is interesting, thanks.

Regarding pine pollen, does pine pollen actually reduce AR? I thought it inhibits or does something to 5AR, which should, in theory, cause AR to rise. I'm still curious about its mechanism of action.

Yeah for testosterone (i.e. TRT) we had a thread in here somewhere where Gbol mentioned that TRT alone upregulates the AR since it converts to estrogen as well. But TRT + aromatase inhibitor actually down regulates the AR since you pushing the DHT pathway which in turn would down regulate the AR.

You are basically doing the opposite action of finasteride (fin increases T by inhibiting 5AR/DHT and pushing estrogen pathway). There was also study where finasteride with aromatase inhibitor was given and it essentially reversed the side effects of finasteride. Same reason why many people on fin take zinc on it for side effects but the hair benefits also get removed as well.

That is why I think TRT gel/cream put on the balls helps people much better versus TRT injections since a lot of that T is converting to DHT on the scrotum and forcing the 5AR/DHT pathway.

For my personal experience with both pine pollen - pine pollen felt more androgenic for me. Like pine pollen would dry my joints out and make my muscles super tight. The opposite of reducing 5AR I found. I think a lot of people had similar experiences to it as well. I think pine pollen is androgenic/anti estrogenic but if you pair it with progesterone/potassium you support both pathways.

a couple MLs of Pine pollen tincture + 100mg oral micronized progesterone daily felt like a mini cycle for me. The progesterone got rid of the dry joint issue and felt really good on it. Basically all androgens cause potassium wasting so that is why you should pair with progesterone/potassium.

 

[RebelWithACause]

I swear finasteride even if you metabolize it it changes your 5ar (semi)permanently in brain unless you stimulate 5ar hardcore again. Even when I did that little experiment after "beating PFS". After I used finasteride for months I felt different again like my 5ar levels in brain were lower than normal but the rest was back to normal. So some of those protocols like cdsnuts and also what Helen recommended they really have merit for people with PFS imo. I think mineral balancing won't fix that personally. Because I did a long time mineral balancing even in that state of PFS and it never changed that low 5AR brain effect. But rest of my health was better.

Then once I stimulated 5ar again hardcore. Like I used Proviron back then felt like it really changed my brain chemistry. Minerals never did that.

 

[Resurection]

Yeah for testosterone (i.e. TRT) we had a thread in here somewhere where Gbol mentioned that TRT alone upregulates the AR since it converts to estrogen as well. But TRT + aromatase inhibitor actually down regulates the AR since you pushing the DHT pathway which in turn would down regulate the AR.

You are basically doing the opposite action of finasteride (fin increases T by inhibiting 5AR/DHT and pushing estrogen pathway). There was also study where finasteride with aromatase inhibitor was given and it essentially reversed the side effects of finasteride. Same reason why many people on fin take zinc on it for side effects but the hair benefits also get removed as well.

That is why I think TRT gel/cream put on the balls helps people much better versus TRT injections since a lot of that T is converting to DHT on the scrotum and forcing the 5AR/DHT pathway.

For my personal experience with both pine pollen - pine pollen felt more androgenic for me. Like pine pollen would dry my joints out and make my muscles super tight. The opposite of reducing 5AR I found. I think a lot of people had similar experiences to it as well. I think pine pollen is androgenic/anti estrogenic but if you pair it with progesterone/potassium you support both pathways.

a couple MLs of Pine pollen tincture + 100mg oral micronized progesterone daily felt like a mini cycle for me. The progesterone got rid of the dry joint issue and felt really good on it. Basically all androgens cause potassium wasting so that is why you should pair with progesterone/potassium.

Yes, I understand what you're talking about, and it's logical and well-described by you. Are you aware of anyone who was cured via the path of HRT + potassium/progesterone

The only thing that's unclear is if finasteride blocks 5ar, then where does all the testosterone go when we inhibit aromatase. Into the remaining 10% of enzymes and DHT?

I thought about the option with progesterone + testosterone, in theory, it should induce both pathways, the androgen pathway and the GABA pathway, perhaps this is more suitable for someone like me.

Speaking about myself, I did not lose my libido. It seems more like an imbalance between 5-alpha reductase type 2 and type 1. Where 5ar2 is high/normal, and 5ar1 is low. All the symptoms are dry skin (no oiliness), liver problems, bile, intestines, mucous membranes, low estrogen, high cortisol, inflammation, etc. Everything that activates the androgen pathway worsens the symptoms, everything that increases estrogen and reduces AR/DHT improves them.
Perhaps androgens continue to work,but allopregnanolone is not produced.

But there are contradictions here. For example, if I reduce AR density, I do not get the same effect as from a 5ar inhibitor. I only get a reduction in inflammation (due to reduced nitric oxide). But logically, 5ar should become higher and progesterone should convert more into allopregnanolone, which then goes to GABA. A 5ar inhibitor does the opposite, it will reduce 5ar and the activation of GABA by allopregnanolone, but on it, I am practically cured, as are many others, which is illogical. Perhaps the testosterone -> estrogen pathway is the most important in my case.

Definitely, one tablet within 5 minutes could not have affected the receptors and it is still very doubtful that it managed to change anything epigenetically, although who knows. In my opinion, it's something with the enzyme itself, the consequences of its metabolism, or what this enzyme uses as a cofactor.

Regarding pollen. I tried pollen and just like you, I first got an androgenic effect, but only at the moment I took it and for some time after. The next day I got an effect like from a 5ar inhibitor. Therefore, I didn't fully understand how it actually works. The only thing I could think of at that moment was that the testosterone in the pollen took a day to start acting and that was the effect of testosterone and estrogen.

There is very little information on pine pollen, maybe it reduces the activity of the enzyme itself, it's not clear.

I remember how some guy on the Ray Peat forum smeared something on his balls and got PFS. I don't remember exactly what it was, some kind of oil I think, but it was a funny case. I think playing around with the testicles, if it's not happening with a woman, will be unpredictable because as you rightly said, it will bind to LH/5AR faster and more strongly. Although, I won't lie, these days there are such women that even with them everything is unpredictable and who knows what is actually worse, losing property, time, children or PFS

 

[Resurection]

I swear finasteride even if you metabolize it it changes your 5ar (semi)permanently in brain unless you stimulate 5ar hardcore again. Even when I did that little experiment after "beating PFS". After I used finasteride for months I felt different again like my 5ar levels in brain were lower than normal but the rest was back to normal. So some of those protocols like cdsnuts and also what Helen recommended they really have merit for people with PFS imo. I think mineral balancing won't fix that personally. Because I did a long time mineral balancing even in that state of PFS and it never changed that low 5AR brain effect. But rest of my health was better.

Then once I stimulated 5ar again hardcore. Like I used Proviron back then felt like it really changed my brain chemistry. Minerals never did that.

That is exactly what I am talking about. In my opinion, two pathways seem logical here.

1. Finasteride gets trapped in the liver and continues to act.

2. The issue is with the systems themselves that are supposed to metabolize the enzyme and synthesize a new one. This could also explain many other syndromes.

I looked into how finasteride is excreted, and it uses glucuronidation (UGT). It seems it doesn't use glutathione conjugation at all, contrary to what was written on the forum about glutathione being needed for the second phase of its detoxification. So, it turns out it's not needed.

It is 39% excreted by the kidneys, with the primary route of elimination being through bile. So, if it gets stuck and blocks the bile, then the kidneys should work overtime and try to excrete it through an alternative pathway.

The problem might lie with P-glycoprotein (Pgp). This transporter is needed in phase 3 detoxification, where it captures xenobiotics on the cell membrane and throws them out. It is induced by PXR, and if we assume that PXR is suppressed by finasteride, then the drug or its metabolites are likely to get stuck and continue to act. This aspect could explain the altered sensitivity to drugs, supplements, etc., in people with PFS/CFS/Long COVID, as Pgp requires a lot of ATP.

Therefore, I previously thought that Vitamin D3 or dexamethasone, through the induction of CYP3A4 and PXR, enhanced Pgp activity and thus people got rid of PFS by removing finasteride from the liver, brain, etc.

Finasteride metabolites work at about 20% of the potency of finasteride itself. So, if we assume it gets stuck, the action should be weaker, but it should presumably still be inhibitory. I don't yet see a reason why re-administering a 5ARI should improve the condition in this scenario—it should cause a worsening.

The fact that re-administering a 5ar inhibitor has treated many people, including me, is in my opinion the most paradoxical thing in all of this.

 

[RebelWithACause]

That is exactly what I am talking about. In my opinion, two pathways seem logical here.

1. Finasteride gets trapped in the liver and continues to act.

2. The issue is with the systems themselves that are supposed to metabolize the enzyme and synthesize a new one. This could also explain many other syndromes.

I looked into how finasteride is excreted, and it uses glucuronidation (UGT). It seems it doesn't use glutathione conjugation at all, contrary to what was written on the forum about glutathione being needed for the second phase of its detoxification. So, it turns out it's not needed.

It is 39% excreted by the kidneys, with the primary route of elimination being through bile. So, if it gets stuck and blocks the bile, then the kidneys should work overtime and try to excrete it through an alternative pathway.

The problem might lie with P-glycoprotein (Pgp). This transporter is needed in phase 3 detoxification, where it captures xenobiotics on the cell membrane and throws them out. It is induced by PXR, and if we assume that PXR is suppressed by finasteride, then the drug or its metabolites are likely to get stuck and continue to act. This aspect could explain the altered sensitivity to drugs, supplements, etc., in people with PFS/CFS/Long COVID, as Pgp requires a lot of ATP.

Therefore, I previously thought that Vitamin D3 or dexamethasone, through the induction of CYP3A4 and PXR, enhanced Pgp activity and thus people got rid of PFS by removing finasteride from the liver, brain, etc.

Finasteride metabolites work at about 20% of the potency of finasteride itself. So, if we assume it gets stuck, the action should be weaker, but it should presumably still be inhibitory. I don't yet see a reason why re-administering a 5ARI should improve the condition in this scenario—it should cause a worsening.

The fact that re-administering a 5ar inhibitor has treated many people, including me, is in my opinion the most paradoxical thing in all of this.

Makes sense yea I did notice when I quit finasteride with the second time/experiment that yes the worst effects were gone after two weeks max. But brain was stuck in low 5ar like I lacked allopregnanolone and whatever else hormone is converted through 5ar. Felt more anxiety than I do now. The experience of anxiety was higher.

Could be that the combo of some hormones in brain being lower while DHT is going back up, that combo could maybe cause people to feel worse. DHT does promote more adrenaline/aldosterone maybe this increases anxiety for some too because you lack GABA in brain to cope with increase in aldosterone/adrenaline/etc. Just brainstorming here it's based on nothing.

DHT promotes feeling of energy too. But 5ar also increases allo and GABA which keeps you calmer under increase in energy. So maybe DHT goes up but you lack the GABA hormones in the brain normally made with 5ar.

Pretty sure DHT is made outside of brain so you now have normal DHT but brain levels of 5ar still low. Maybe even causes low DHT in brain. So you got high DHT running through your veins but nothing to support the brain while this happens

That's why TRT doesn't work. You just add more hormones to the mix but same thing keeps happening with conversion in brain.

Fin for me lowered metabolism and cortisol. For others/different cases maybe increases it. So I went back on it felt better mostly just lower cortisol, lower metabolism. Energy levels were lower but more stable. Plus I think because I had low 5AR still in the brain this could of balanced it more temporarily. Once I took too much finasteride I felt way worse than the sweet spot and even felt worse than being off it completely.

 

[Aflac94]

Awesome post. @Resurection
I’m a one piller too (only ever took 1 total pill). For me I crashed immediately after taking too (mildly) felt so messed up for 1 week. Then I felt normal almost super human for 3 months. Then in middle of night one night massive crash. Like gaba stopped and glutamate turned on in middle of night , never slept the same or felt same since
(Was in med school so super stressed, used thc prior to crash , also had concussion learning up to it)

So you feel better on fin? Do you take it?
Anything that has cured you helped you ? Or idea on getting bile working again? When I was young has the perfect dark stools but only a few times a year these days

High dose prednisone for a few days is the only thing that really felt did something to change things up in brain but not cured. And I had side effects from it I think so afraid to try again. Did a small stool transplant with my 3 month, then 1 year old son’s stool (figured safe donor). Gave me a bit more energy but no cure. In some ways felt bad even after

 

[Aflac94]

Mom had amniocentesis to see if I had Down syndrome because she was 35. (Stupid doctors and American medical industry…I’m now a family doctor ironically) and water broke at 20 weeks. She hung on till 32 weeks, but I was obviously born premature; so my mom was given steroids and all kinds of drugs before and during my birth (tocolytics , pitocin)

I wonder if the medicalization of the birthing process affects mess up a lot of our chemistry from birth. 30 percent of moms are given antibiotics at birth now too which is wild

Or maybe it all has nothing to do and it’s genetics passed down , or lifestyle, idk

 

[Resurection]

Makes sense yea I did notice when I quit finasteride with the second time/experiment that yes the worst effects were gone after two weeks max. But brain was stuck in low 5ar like I lacked allopregnanolone and whatever else hormone is converted through 5ar. Felt more anxiety than I do now. The experience of anxiety was higher.

Could be that the combo of some hormones in brain being lower while DHT is going back up, that combo could maybe cause people to feel worse. DHT does promote more adrenaline/aldosterone maybe this increases anxiety for some too because you lack GABA in brain to cope with increase in aldosterone/adrenaline/etc. Just brainstorming here it's based on nothing.

DHT promotes feeling of energy too. But 5ar also increases allo and GABA which keeps you calmer under increase in energy. So maybe DHT goes up but you lack the GABA hormones in the brain normally made with 5ar.

Pretty sure DHT is made outside of brain so you now have normal DHT but brain levels of 5ar still low. Maybe even causes low DHT in brain. So you got high DHT running through your veins but nothing to support the brain while this happens

That's why TRT doesn't work. You just add more hormones to the mix but same thing keeps happening with conversion in brain.

Fin for me lowered metabolism and cortisol. For others/different cases maybe increases it. So I went back on it felt better mostly just lower cortisol, lower metabolism. Energy levels were lower but more stable. Plus I think because I had low 5AR still in the brain this could of balanced it more temporarily. Once I took too much finasteride I felt way worse than the sweet spot and even felt worse than being off it completely.

Yes, something happens to the enzyme itself and possibly only in the brain. If the brain does not send a signal, then the AR receptors in the genital organs will upregulate, which is what we have seen in studies. In the body itself, DHT and 5AR might be fine, there is just no signal. So I think you are right in your reasoning. This explains the fact that the recovery of libido and penile function in people happens quickly, as soon as a person activates this signal. Testosterone works, it binds to the AR, otherwise there would be problems with the heart, so it seems only the DHT system and neurosteroids are affected.

Regarding 5ARI (if we assume homeostasis and epigenetics as the basis). Perhaps the body arrives at a new homeostasis while you are taking finasteride. The body adapts to the drug (low 5ar) and when the drug leaves, the body itself remains in the chemistry of finasteride. Taking the drug again kind of returns the person to that chemistry the body got used to, and the person feels "cured". I would probably compare this to PTSD.

So (for example), fin inhibits 5ar, the body produces more T and progesterone and less DHT and neurosteroids. GABA A (possibly GABA B as well) and AR upregulate. Discontinuing the drug returns the enzymes to their original state, but the body's homeostasis remained as it was on finasteride. An adaptation to the work of the enzymes occurs, but not a change in the overall homeostasis, which is why what people feel as a "crash" happens. In reality, in this case, I assume the body continues to work as on finasteride, but with working 5ar enzymes.

As far as I remember, this is Helen theory, he suggested that a strong flow of DHT through the overexpressed AR receptors after drug discontinuation, turns them off at the gene level, because the body is not able to cope with this flow and this is logical, since people do not just get impairments in the form of reduced libido and erection, their member and libido literally completely turn off, and the connection between the brain and the genitals is lost. I heavily downregulated AR, this reduced libido, there were difficulties with erection and achieving orgasm, also the connection was lost a bit, but this is not even close to what happens to people. Also, there were some problems with blood vessels and heart palpitations, since I downregulated AR systemically, so Tubzy is right, if you pressure the receptor, it should be with DHT or its analogs. Can we bring the same thing to GABAR?

But speaking about this theory, some people took fin several times, and they could take it for years, stop, recover normally, and then, for example a year later, take it again and only then get the "crash". People also suffer not only from AR issues (member, libido, etc) but also from neurosteroids.

We have seen in studies that people have almost no allopregnanolone and a loss of many neurosteroids, which is not entirely clear, how it happens with the loss of AR signal. 5AR increases for DHT to try to bind, but decreases for neurosteroids? It's doubtful, considering that DHT is low in many people.

Again, how does the crash from 1 tablet fit here. Many also have a worsening after they took a 5ARI again, which looks more like getting stuck and accumulation, than a new homeostasis.

It is also not clear why for some the connection between the brain and the member disappears, for others the problem is only with neurosteroids, considering that finasteride inhibits 5ar2 more strongly. Is it about the initial metabolism (for example having POIS and inflammation, as in my case) or is it a genetic moment here.

When I think about all of them at once, through the prism of metabolism and the hormonal/receptor cascade, I see nothing but solid paradoxes. More questions than answers. Besides a disruption in the work of the enzyme itself or its metabolism, little else fits here (in my opinion). Of course, we can take into account that everyone is unique and it's all about different metabolisms, but obviously, for most people such disruptions do not occur when they take this drug, and if we talk about uniqueness, then we initially have impaired certain systems before we fall into this, and already here, these systems can be impaired in everyone, through "unique" paths for them.

I read your topic a bit and as far as I understood, you cured yourself with dexamethasone? When you say you took finasteride a second time, do you mean after you were cured or was it before you got PFS?

 

[Resurection]

Awesome post. @Resurection
I’m a one piller too (only ever took 1 total pill). For me I crashed immediately after taking too (mildly) felt so messed up for 1 week. Then I felt normal almost super human for 3 months. Then in middle of night one night massive crash. Like gaba stopped and glutamate turned on in middle of night , never slept the same or felt same since
(Was in med school so super stressed, used thc prior to crash , also had concussion learning up to it)

So you feel better on fin? Do you take it?
Anything that has cured you helped you ? Or idea on getting bile working again? When I was young has the perfect dark stools but only a few times a year these days

High dose prednisone for a few days is the only thing that really felt did something to change things up in brain but not cured. And I had side effects from it I think so afraid to try again. Did a small stool transplant with my 3 month, then 1 year old son’s stool (figured safe donor). Gave me a bit more energy but no cure. In some ways felt bad even after

Hello, it seems I have a lot of questions for you)

When you say you were a "superhuman" do you remember, did you feel androgens or GABA? Or both? Can you describe it in more detail?

Also interesting, you said the crash happened at night, were you awake at that moment? Do you remember what happened in detail before your body changed? Here I mean both the sensations themselves and what you might have been doing before that. Perhaps there was certain food, an orgasm, strong stress, workouts, etc.?

Also what dose did you take and was there a problem with sensitivity to substances before taking finasterid? For example, a low dose of any drug or supplement could feel like a high dose.

It's just an interesting case. Finasteride, after discontinuation, logically raised 5ar and gave you more of its metabolites. If the receptors were overexpressed, then the body perceived everything in an enhanced way, hence the feeling as you put it of a "superhuman". Then you get a crash. This would be logical if you had taken it for a long time, but this is just 1 tablet and it would be logical if it happened within a week, but for you it took 3 months.

I would suggest trying wormwood or bacopa, this should increase sensitivity to GABA A and it should get easier, if the issue is low GABA activity. But people with PFS can also have receptor overexpression. I personally like wormwood more, but it inhibits the receptor, so some people need to be careful with it, figuring out the doses experimentally, starting with a low one.

Yes, that's right, I am talking about restoring digestion and giving the body everything it needs, while this digestion is working. It's just that people have it impaired in different ways, for some it's bile, for others acidity, for others everything together, and the specific impairments themselves can differ.

Take Tubzy for example, his main problem was alkalosis and low acidity, he felt improvements when he started taking HCL and potassium. Before that, as I understand it, he tried a lot, including hormones. Then he continued and gave the body everything it needed from food, so that the body itself would distribute everything. According to him, what cured him was mainly amino acids, which is logical since without acid they weren't being broken down all that time, but I think methylation also played a big role here, through spinach (folates) and potassium which he was taking, and also the bile which he activated with randro. This is of course my opinion based on what he wrote in his thread, maybe he will read this and say that I am actually mistaken.

So, he had such a problem, another person might have Helicobacter and the solution will be different. I by the way saw one guy on the pfs forum cure Helicobacter and his PFS went away.

The same goes for bile, for some taurine doesn't work (no cysteine) and no conjugation, for others glycine, maybe no choline, cholesterol, etc. That is, a problem with the bile acids themselves. For some, with the p450 enzymes and ATP themselves (CFS). And somewhere the flow itself might be blocked, by norepinephrine for example, which simply constricts it (Sphincter of Oddi). And there is a lot of norepinephrine, because there is a lot of glutamate and excitation due to impaired GABA and allopregnanolone synthesis. In addition to this, a person might also have low methylation, the PNMT enzyme is slow, no conversion to adrenaline, and fat metabolism is impaired.

I think everyone needs to figure out where their weak spot is in this matter.

The main task (in my opinion) is to give everything necessary, but before that create the conditions for the body to start absorbing it all. That's the idea. I think it can also be treated with hormones, but it's hard to say how exactly that would work, it's not without risks.

 

[Aflac94]

Hello, it seems I have a lot of questions for you)

When you say you were a "superhuman" do you remember, did you feel androgens or GABA? Or both? Can you describe it in more detail?

Also interesting, you said the crash happened at night, were you awake at that moment? Do you remember what happened in detail before your body changed? Here I mean both the sensations themselves and what you might have been doing before that. Perhaps there was certain food, an orgasm, strong stress, workouts, etc.?

Also what dose did you take and was there a problem with sensitivity to substances before taking finasterid? For example, a low dose of any drug or supplement could feel like a high dose.

It's just an interesting case. Finasteride, after discontinuation, logically raised 5ar and gave you more of its metabolites. If the receptors were overexpressed, then the body perceived everything in an enhanced way, hence the feeling as you put it of a "superhuman". Then you get a crash. This would be logical if you had taken it for a long time, but this is just 1 tablet and it would be logical if it happened within a week, but for you it took 3 months.

I would suggest trying wormwood or bacopa, this should increase sensitivity to GABA A and it should get easier, if the issue is low GABA activity. But people with PFS can also have receptor overexpression. I personally like wormwood more, but it inhibits the receptor, so some people need to be careful with it, figuring out the doses experimentally, starting with a low one.

Yes, that's right, I am talking about restoring digestion and giving the body everything it needs, while this digestion is working. It's just that people have it impaired in different ways, for some it's bile, for others acidity, for others everything together, and the specific impairments themselves can differ.

Take Tubzy for example, his main problem was alkalosis and low acidity, he felt improvements when he started taking HCL and potassium. Before that, as I understand it, he tried a lot, including hormones. Then he continued and gave the body everything it needed from food, so that the body itself would distribute everything. According to him, what cured him was mainly amino acids, which is logical since without acid they weren't being broken down all that time, but I think methylation also played a big role here, through spinach (folates) and potassium which he was taking, and also the bile which he activated with randro. This is of course my opinion based on what he wrote in his thread, maybe he will read this and say that I am actually mistaken.

So, he had such a problem, another person might have Helicobacter and the solution will be different. I by the way saw one guy on the pfs forum cure Helicobacter and his PFS went away.

The same goes for bile, for some taurine doesn't work (no cysteine) and no conjugation, for others glycine, maybe no choline, cholesterol, etc. That is, a problem with the bile acids themselves. For some, with the p450 enzymes and ATP themselves (CFS). And somewhere the flow itself might be blocked, by norepinephrine for example, which simply constricts it (Sphincter of Oddi). And there is a lot of norepinephrine, because there is a lot of glutamate and excitation due to impaired GABA and allopregnanolone synthesis. In addition to this, a person might also have low methylation, the PNMT enzyme is slow, no conversion to adrenaline, and fat metabolism is impaired.

I think everyone needs to figure out where their weak spot is in this matter.

The main task (in my opinion) is to give everything necessary, but before that create the conditions for the body to start absorbing it all. That's the idea. I think it can also be treated with hormones, but it's hard to say how exactly that would work, it's not without risks.

Apologies in advance for hijacking thread part one:

I think I got a tablet of proscar tablet because it was cheaper than Propecia from a derma. I broke into fourths and took one fourth . Don’t know if I was just psyched out or stress from school but I think it was real now knowing the harms of this stuff but I couldn’t sleep had insomnia for like a week , just fell off but don’t remember any type of crash per se but it was March 2016 so it’s hard to remember detail details. thought I screwed up my life and then all of a sudden I remember I felt normal after about a weekand I was so thankful that I escaped and ashamed I was careless with my health and decided I would never take that again and I never did.

Unfortunately three months later I did have a massive crash. I didn’t think anything of it at the time but leading up to that I feel a little bit unstable I remember waking up in the middle of the night which wasn’t too usual for me having to pee and crazy thirsty I would have to keep water on my nightstand and go to the bathroom and then I would get back into a deep amazing sleep. That was unusual for me however the thirst and waking up at night.

In general myself before PFS think I had some kind of hypersomnia problem cause I was an insanely deep sleeper it almost felt like I was entering a different universe when I went to sleep, only negative was waking up was pretty brutal and I did feel like I fell asleep a lot inappropriately throughout the day at times like in class or library. But I didn’t have a disease or full on narcolepsy it just felt good to sleep and restorative. Although I don’t know if this is quite common but I wouldn’t always wake up in the morning not in the right point of my cycle and sometimes would feel sleepy throughout the day, occasionally I would wake up at the exact perfect time or without my alarm and feel like I was perfectly rested. I think some people had that all the time which would’ve been amazing.

Pre-PPFS history: don’t recall major health problems until when I was in high school just before I started getting concussions from playing ice hockey. Probably starting age 14 and on through 18. Probably had like 10 concussions. Also probably approximately 16 I began to get migraines with aura. Around that time or possibly later in early 20s, as well I had irritable bowel type symptoms or like a tightness feeling in my bowels. I went test and there was nothing structurally wrong. Diagnosed IBS. So the concussions, migraines, not waking up on the right sleep cycle/hypersomnia, irritable bowel.

My relationship with substances: never on prescription medications as a kid although I probably took the normal things like an occasional anabiotic, Tylenol, ibuprofen cough medicine whatever stuff like that which I don’t necessarily see as benign anymore. But I don’t remember being hypersensitive to meds or anything although like I said I didn’t take a lot of of them. Regarding alcohol I was a typical college kid after age 18 and heavily drank from 18 up to my crash, I mean socially I wasn’t drinking every day or low in my room. But nearly every other weekend. Which I deeply regret now definitely wonder if that could be a reason why a lot of people are unhealthy as they grow older into do adulthood, that type of culture of binge drinking. Even remember a night when I drink someone’s homemade moonshine and felt especially horrific after. I guess to get at your question in the sense of substances feeling intense I would say Sleep and gaba system was sensitive because sleep was so intense and alcohol was so intense I didn’t need to drink much and I would get very intoxicated, and I slept so deeply in general. And these are the symptoms that have been broken especially the sleep, instead of a transition and almost haze feeling going into sleep I’m almost immediately awake when I wake up from sleep like the brain’s already turned on, there’s no transition or haze or sleepy feeling. Which is just so different than it was before. I guess one positive is it it’s easier to wake up but it doesn’t feel as restorative. For the longest time I drank alcohol and it did absolutely nothing felt like drinking water. It still doesn’t affect me like I did before but I did test it on one occasion and I overdrunk tremendously 2 years ago post pfs and I did get extremely intoxicated so I at least works now which may have been my health overall improving but it’s not the same as before takes a lot and only sometimes feel effects.

 

[Aflac94]

When you say you were a "superhuman" do you remember, did you feel androgens or GABA? Or both? Can you describe it in more detail?

Also interesting, you said the crash happened at night, were you awake at that moment? Do you remember what happened in detail before your body changed? Here I mean both the sensations themselves and what you might have been doing before that. Perhaps there was certain food, an orgasm, strong stress, workouts, etc.?
—————————/
Hard to remember again cause it was only one week about 10 years ago but I think it was more androgens than GABA I remember feeling the workouts in the gym way more and although I say I felt superhuman I felt kind of unstable I don’t really know how to describe that but like my system was kind of amped up inappropriately.

Leading up to the crash I resume my normal life which was binge drinking weekends; keeping crazy hours studying for exams in med school sometimes pulling all nighters to study before an exam. So not healthy. But I felt normal. Also I took trip to Canada I remember and someone offered me a joint and I rarely ever smoke weed maybe one or two other times in my life I took a hit don’t know if that’s anything significant.

Regarding the actual crash I was dead asleep and I woke up like I’ve never woken up before without like a sleep haze or sleepy feeling upon waking but on this occasion in the middle of the night I was suddenly awake in a sense I’ve never experienced before. I don’t really know how to characterize it , waking up as like turning on a light switch and normally you’re turning on slowly on this occasion in the middle the night it was immediately flicked on. I also think I had to pee a lot right then and there and I was thirsty like those times I was referring to leading up to this when I would wake up in the middle of the night but those other times I just went back to sleep had a normal sleepy feeling and got right back to sleep.

I felt so bad in indescribable way I almost went to the ER but I didn’t because I didn’t know what was going on and there wasn’t like one symptom to pinpoint like pain or something. Everyone knows the rest of the story nothing ever went back to normal and I’ve just been probably slowly adapting to this new body chemistry ever since and made minor improvements over 10 years but the core disruption or imbalance or dys- regulation, whatever etc seems to remain.

Resvertrol R-andro was cycling those once and had a window for one day maybe. You can click on my log and maybe some other details in the thread I created PFS 2016 crash, prob not much but Helen took it over on page 7 and some interesting discussions from there

 

[Aflac94]

Sidenote but does anybody else think that with AI we could get some answers on what exactly went wrong or maybe like a treatment in next 10 years. Try putting stuff into ChatGPT but nothing amazing yet. Picture seems a bit more hopeful with that technology. Probably with a lot of other health conditions too

 

[Aflac94]

“ Then you get a crash. This would be logical if you had taken it for a long time, but this is just 1 tablet and it would be logical if it happened within a week, but for you it took 3 months.”

I feel like I remember reading somewhere that it took severe months to regenerate enzyme or something. I always thought that maybe at the 3 month mark the enzymes that were messed up came back online and it overloaded the system or down regulated the over expressed receptors while my body was used to the over expressed chemistry so then the crash or something along those lines.

 

[Resurection]

Apologies in advance for hijacking thread part one:

I think I got a tablet of proscar tablet because it was cheaper than Propecia from a derma. I broke into fourths and took one fourth . Don’t know if I was just psyched out or stress from school but I think it was real now knowing the harms of this stuff but I couldn’t sleep had insomnia for like a week , just fell off but don’t remember any type of crash per se but it was March 2016 so it’s hard to remember detail details. thought I screwed up my life and then all of a sudden I remember I felt normal after about a weekand I was so thankful that I escaped and ashamed I was careless with my health and decided I would never take that again and I never did.

Unfortunately three months later I did have a massive crash. I didn’t think anything of it at the time but leading up to that I feel a little bit unstable I remember waking up in the middle of the night which wasn’t too usual for me having to pee and crazy thirsty I would have to keep water on my nightstand and go to the bathroom and then I would get back into a deep amazing sleep. That was unusual for me however the thirst and waking up at night.

In general myself before PFS think I had some kind of hypersomnia problem cause I was an insanely deep sleeper it almost felt like I was entering a different universe when I went to sleep, only negative was waking up was pretty brutal and I did feel like I fell asleep a lot inappropriately throughout the day at times like in class or library. But I didn’t have a disease or full on narcolepsy it just felt good to sleep and restorative. Although I don’t know if this is quite common but I wouldn’t always wake up in the morning not in the right point of my cycle and sometimes would feel sleepy throughout the day, occasionally I would wake up at the exact perfect time or without my alarm and feel like I was perfectly rested. I think some people had that all the time which would’ve been amazing.

Pre-PPFS history: don’t recall major health problems until when I was in high school just before I started getting concussions from playing ice hockey. Probably starting age 14 and on through 18. Probably had like 10 concussions. Also probably approximately 16 I began to get migraines with aura. Around that time or possibly later in early 20s, as well I had irritable bowel type symptoms or like a tightness feeling in my bowels. I went test and there was nothing structurally wrong. Diagnosed IBS. So the concussions, migraines, not waking up on the right sleep cycle/hypersomnia, irritable bowel.

My relationship with substances: never on prescription medications as a kid although I probably took the normal things like an occasional anabiotic, Tylenol, ibuprofen cough medicine whatever stuff like that which I don’t necessarily see as benign anymore. But I don’t remember being hypersensitive to meds or anything although like I said I didn’t take a lot of of them. Regarding alcohol I was a typical college kid after age 18 and heavily drank from 18 up to my crash, I mean socially I wasn’t drinking every day or low in my room. But nearly every other weekend. Which I deeply regret now definitely wonder if that could be a reason why a lot of people are unhealthy as they grow older into do adulthood, that type of culture of binge drinking. Even remember a night when I drink someone’s homemade moonshine and felt especially horrific after. I guess to get at your question in the sense of substances feeling intense I would say Sleep and gaba system was sensitive because sleep was so intense and alcohol was so intense I didn’t need to drink much and I would get very intoxicated, and I slept so deeply in general. And these are the symptoms that have been broken especially the sleep, instead of a transition and almost haze feeling going into sleep I’m almost immediately awake when I wake up from sleep like the brain’s already turned on, there’s no transition or haze or sleepy feeling. Which is just so different than it was before. I guess one positive is it it’s easier to wake up but it doesn’t feel as restorative. For the longest time I drank alcohol and it did absolutely nothing felt like drinking water. It still doesn’t affect me like I did before but I did test it on one occasion and I overdrunk tremendously 2 years ago post pfs and I did get extremely intoxicated so I at least works now which may have been my health overall improving but it’s not the same as before takes a lot and only sometimes feel effects.

Thank you for not being lazy and describing the whole story, it is interesting. It is truly amazing how people experience the crash so differently.

I would single out IBS and concussions as the possible initial problem. IBS is essentially often SIBO itself, or it is a problem with serotonin (exciting 5ht2 receptors) where motility is too active. You mentioned taking some antibiotics, that could theoretically have caused a problem with the gut.

Regarding concussions, I cannot say much as I do not fully understand how exactly an injury can affect the brain, it is quite unpredictable.

As for assumptions, since you had sleep problems, perhaps there are issues with orexins or, for example, with galanin

Orexins are essentially regulators of wakefulness, it is they that prevent you from just falling asleep easily, and they also stimulate digestion, energy production, and the motivation to search for that very food. This happens in narcolepsy, exactly when orexin neurons die, a person can just randomly fall asleep somewhere (I think you know that yourself).

But galanin, this seems similar to what you are describing, when there is no smooth transition into sleep and recovery. Neurons in the hypothalamus synthesize galanin, these same neurons activate GABA and galanin, which inhibit all excitatory neurotransmission (norepinephrine, histamine, serotonin). This is how a person prepares for sleep and falls asleep.

Essentially, orexins are activity (wakefulness). Galanin is the reduction of activity (sleep). There could be an imbalance here, and GABA with glutamate are equally important. They all work in the hypothalamus, and a concussion, I assume, could have disrupted something there, then (for example) you took Finasteride and further disrupted GABA regulation. Perhaps you precisely lack normal sleep for PFS recovery, because the same galanin, although it seems to be just signaling molecules, actually triggers these recovery processes. The body produces growth hormone, reduces stress (cortisol regulation), turns on ATP production, and activates brain detoxification (the glymphatic system).

The synthesis of this peptide requires a lot of things in its stages, I looked it up and it needs all 29 amino acids, ATP, iron, zinc, copper, manganese, vitamin C, B6. Activation can occur through estrogen, cortisol, circadian rhythms. The enzyme PAM is important, meaning vitamin C is needed.

I assume, after Finasteride, GABA activity was high and it seems the issue is with the receptor, it upregulated. I asked if the sensitivity to the drug changed, for the reason that it is strange for so many receptors to change so much from just 1 pill. I have the same issue, receptor regulation is impaired and sensitivity to drugs is super high, compared to a normal person with PFS, because of this regulation happens even with tiny doses. But it is quite possible that GABA was initially impaired for you and it does not control receptor regulation.

Migraines seem like acetylcholine, acetylcholine is also involved in sleep. It is needed for the REM phase and for dreaming itself. I remember some guys on a forum inhibited acetylcholinesterase, their acetylcholine increased and they "lived" in lucid dreams, funny.

The fact that you wanted to drink and constantly went to the toilet is interesting, it speaks about fluid metabolism. I think it is a sodium problem, meaning Finasteride affects sodium after discontinuation and apparently potassium. Sodium is lost with urine, fluid is not retained, the body asks for water and at the same time constantly excretes this water because it cannot hold it. And you said this happened during sleep I just did not see you write that when you were awake you constantly drank water and went to the toilet.

It seems to me, either Finasteride disrupts the balance of 5-beta and 5-alpha reductase and 5-beta becomes high after discontinuation, this constantly metabolizes aldosterone. Or when Finasteride inhibits 5AR, the metabolism of aldosterone becomes lower, aldosterone rises and downregulates the receptor, after discontinuation the receptor is low and sodium is lost. Or maybe there is already a problem with progesterone, for example the GABA A receptor became high after discontinuation, progesterone became more, this inhibited aldosterone and sodium was lost, while potassium was retained. It is interesting why only during sleep.

Alcohol, yes, when there was a reaction to it, it speaks of high GABA and conversely, the fact that it is not there now, speaks of GABA being ultimately switched off. Overall, it looks as if you took the drug, your receptors went up, you lived on them for some time, and then they sharply dropped and now you have low sensitivity of the receptors specifically. This explains why you could get a reaction to alcohol, if they were completely switched off, that would not have happened. Maybe you really should just try to raise them and see what happens Randro, it is a GABA agonist, it will reduce GABA A sensitivity. Maybe something is also happening with GABA B and then try, for example, GHB, I heard some people were cured with it.

I still did not understand, did you smoke weed long before the crash itself (which happened at night) or was it on the eve, maybe a day before

I actually do not quite see a typical PFS, there is no inflammation, no loss of libido, obviously there is a problem with GABA and possibly progesterone. I will read your thread when I have time, look at what that guy wrote and probably reply there.

 

[highserotonin90]

@Resurection

Great thread.

I've been stuck with acetylcholinesterase inhibition for a year and a half.