Does anyone remember if the Harvard study looked extensively into cortisol?
You can find a list of CYP3A4 inducers/inhibitors on the internet. We should see what the studies indicate about this enzyme. We may need to induce it (or inhibit it) and replace some hormones and let those hormone metabolites increase.
I took an antibiotic a few days before I took fin and then got PFS. I’m guessing the antibiotic may have messed with the CYP3A4 enzyme. Many others report the same thing.
St John’s Wort is an inducer of CYP3A4:
ncbi.nlm.nih.gov/pubmed/10824623
Took it for about 6 months. Helped with depression, did nothing for physical side-effects.
All the people who recovered fixed their diet. It seems that inflammation may play a large role in PFS. Cortisol is the bodies anti-inflammatory and if we have problems with cortisol, it’ll be harder to beat the inflammation. If one of the enzymes that deals with cortisol metabolism is messed up, we most likely will have to address that.
I have arrived to this. And Im writing the rest, where i explain some lab values that are common to PFS, like vitamin D and 3adiolG. My own conclusions are in orange and at the end.
Finasteride Metabolism
Finasteride’s metabolism is hepatic. It’s metabolites are excreted through feces (39%) and urine (57%). [1]
In Phase I of liver detoxification, finasteride is primarily metabolised through CYP3A4, through Oxidative Metabolism, into:
In Phase II
Hydroxy Finasteride is metabolised into Omega-Hydroxy-Finasteride [3] through Gluthatione S Transferase Omega 1 (GSTO1 gene).
Carboxy Finasteride, which is ± oic finasteride, is then metabolised into Omega-oic-Finasteride [3] through Gluthatione S Transferase Omega 1 (GSTO1 gene).
Glucuronidation:
In Vitro, Omega-Hydroxy-Finasteride is metabolised into omega-hydroxy-finasteride-glucunoride, by UGT1A4. This metabolite was not detected in vivo. [3]
In vivo, omega-oic-finasteride is transformed in omega-oic-finasteride glucuronide and was found in the bile of a few individuals. [3]
Other metabolites
In vitro, but also in urine and bile, 2 other Hydroxy Finasteride compounds were identified. [3]
CYP, UGT and Finasteride
Finasteride is primarily detoxified through CYP3A4.[1]
However, finasteride can also be an inhibitor of CYP3A4 [4]:
This means that high dosage of finasteride might inhibit CYP3A4, which means that finasteride might prevent its own metabolism [4], thus promoting drug accumulation.
Inhibition of hepatic UGT isozymes by finasteride has not been explored before 2014. In vitro, of the seven hepatic UGTs, finasteride potently and selectively inhibited UGT1A4, finasteride did not inhibit hepatic UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15 activities. However, the C max of finasteride in patients is much lower than K i of finasteride for UGT1A4, finasteride is unlikely to cause clinically significant drug–drug interactions via UGTs inhibition. [5]
However, Cmax of finasteride seems to be able to change based on other factors. [6]
In this case
. Even though finasteride and terazosin are not substrates for the same enzyme (CYP3A4).
That could mean there is a metabolite of finasteride that is detoxified by another CYP enzyme, or UGT enzyme, that terazosin either induces or inhibits. This could mean there is a method of detoxification of finasteride that has not been yet identified. It could be a metabolite that has not been yet identified and uses enzymes other than UGT1A3 or CYP3A4.
Conclusion
Genetic polymorphisms in the detoxification elements of the liver, unique to each person, promoted accumulation of high dosages of the drug. This in turn lead to all sorts of problems, some of which are not identified yet.
I think we have a genetic predesposition, be it through methylation blocks, reduced amounts of CYP3A4, UGT1A3, or other enzymes necessary by the metabolites, which were already present or that were latent and were then triggered by the hormonal changes imposed by finasteride. This induced enough drug accumulation that finasteride started inhibiting CYP3A4, preventing it’s metabolism and promoting huge quantities of the drug in the liver. This had lead to the following:
-> Bile acid synthesis problems
-> Liver endoplasmatic reticulum stress
-> Hepatotoxicity
-> Leyidig Cell hyperplasia and adenomas [7]
-> others unidentified
And to it’s consequences:
Liver problems (bile acid problems, liver endoreticulum stress) could be accountable for low vitamin d, high cholesterol, problems with glucuronidation, endoplasmatic reticulum stress, low 3adiolG, digestion issues, high crp, adrenal problems, malabsorption of nutrients and minerals, pancreatitis…
Endoreticulum Stress may have triggered Dolichol Deprivation, as outlined by TryingNotToWorry [8], or could be the other way around.
In rats, finasteride was randomly associated with Leydig Cell hyperplasia and adenomas, as outlined by Vicentv in PropeciaHelp.[7]
The fact that in the mitotane study, the person doesn’t get back the full amount of the CYP3A4 activity, probably could be further indicative of an epigenetic change in that enzyme’s activity. [9]
[1] en.wikipedia.org/wiki/Finasteride
[2] diva-portal.org/smash/record … swid=-4682
[3] researchgate.net/publication … ectrometry
[4] ncbi.nlm.nih.gov/pmc/articles/PMC2740403/
[5] ncbi.nlm.nih.gov/pubmed/25448279
[6] ncbi.nlm.nih.gov/pubmed/9824790
[7] ncbi.nlm.nih.gov/pubmed/8005373
[8] viewtopic.php?f=27&t=4892
[9] press.endocrine.org/doi/full/10. … .2012-2851
Wow so insightful. One of the best reads yet on this forum. Certainly explains why some people have a higher tolerance to the drug than others and our common list of side effects. I was recently identified as having spots on my liver so that supports the build up of the foreign toxin. So even supplementing the larger building blocks like vitamins doesn’t sound like it goes deep enough. We are talking enzymes and even smaller working parts?
So… what do we do to fix this then?
first i need to gather data from blood exams, it will take a while…just so to try to prove this. i already found some
first this theory needs to be proven…
And interesting about the vitamin D. I supplemented for months and got my level
Up to 50. I tested two weeks later after stopping the supplement and it decreased to 30. Dr. Irwig didn’t think it unusual but only two weeks to decrease 40% seemed outrageous after months of 5000ius a day. Something indeed is lowering our D levels substantially.
I have already 3 cases of proven hepatotoxicity from frinasteride
Woop wooop i think my theory is sound
How high of a dose is high? I and many others only took a few pills. I only ingested 5 mg total.
Yeah that is one of the big mysteries in all this. I probably took 5000mg total over the course of twelve years. If these enzymes are so crucial to the metabolic process, just seems so improbable to have the entire system collapse after a handful of pills. My situation I assume is more common as I tolerated high levels of the damage before I crashed. The idea of the genetic predisposition clearly comes into play as my best friend stopped two years of propecia use with no problem. We can use him for studies later. Effing Merck knew damn well what this drug was capable of, even people at the FDA knew Im sure too. But not to hijack the thread, awesome insight into the underlying biology. It all is making more sense, and I think the study you sighted is close enough to see how the broken enzymatic chain makes us resilient to T supplementation. Million dollar question is how to fix this broken web?
If your theory is right then how can PFS be fixed ?
Some briiliant scientist will have to work backwards on this until a feasible path that led from ingestion to our system shutdown response is established. Hopefully this first round of studies can at least identity whether amy metabolites and enzymes have been preserved in their normal state and can’t do their jobs because homeostasis has been disrupted, or whether they have been altered and need some fancy bioengineering breakthrough to reset. Any homeopathic doctor could look at our blood levels and most of us would have low vitamin levels that imply malabsorbtion and chronic inflammation that only compounds our lethargy and anxiety. That is why guys are probably improving through diet and exercise, a not so revolutionary concept, that puts less stress on a damaged liver and has the best shot at reducing chronic inflammation. That is the current fix that everyone should be doing. The complete fix could take some time, but the PFS docs for the most part are so focused on hormone levels that as we better understand which organs have been effected, it will naturally lead at improving larger pieces of the puzzle. So these theories show how complex it is, but there is hope that much more can be done for symptom relief than what is currently being done. To say our issue is hormonal or neuro hormonal is probably probably way to simplistic and flat out wrong at this point. More like unknown disturbances that have altered hormone response and brain functioning is more like it. But also sounds like our collective heads are shedding light. I’m so impressed at the dedication of this forum. You guys Rock!!!
Up until now ive only tried to understand what has happened. Unfortunately i am not sure this explains what is happening! Those are two different things. Im trying to understand that now… When i have further ideas ill write then here
I don’t see how hepatotoxicity would cause a specific block in conversion of neurosteroids at the 5 ar enzyme site. Maybe 5 ar in liver isn’t working, but it doesn’t explain the specific neurosteroid profile seen so far in PFS patients.
why doesn’t it? how do you know the problem is deficient 5ar? give me some more details. you’re assuming things.
you are even the perfect candidate for my consolidation of data as you took this drug just a few days. do you have blood exams? send me a link pls
ahh…let me see if i can summarize this…tomorrow ill perfect it and put in all the references…still i miss one connection which i couldn’t find anywhere: finasteride and foxa2
So… Consider a person with a rare subset of polimorphisms on several steps of the liver detoxification process. Let’s say:
Phase I: -/- for CYP2D6 (this leads to increased estrogen)
Phase II: -/- for GSTO1 (this metabolises a finasteride metabolite), -/- for UGT1A3(this metabolises a finasteride metabolite’s metabolite)
Others: -/- for Pregnane X Receptor (which I am btw…this is affected by fin in high dosages), -/- for SOD2 (this leads to increase of super oxide, which is a ROS), Methylation block SNPs
This very unlucky person, takes a few mgs of finasteride:
Finasteride------------->Carboxy-Finasteride---------------->Omega Oic Finasteride------------------>Omega Oic Finasteride Glucuronide
____________CYP3A4_______________________GSTO1__________________________UGT1A3
Omega Oic Finasteride Glucuronide is found in human bile.
GSTO1 reaction takes place in the mitochondria of hepatocytes. GSTO1 generates ROS.
In a person with mitochondrial detoxification polimorphisms. In this case lets consider SOD2. This leads to impaired reduction of Super Oxide because of low presence of Super Oxide Dismutase. This directly leads to higher presence of Super Oxide because it’s not being reduced properly and Super Oxide is a ROS. So this leads to increase in ROS in the mitochondria.
SOD2 -/- -->Impaired reduction of Super Oxide–>ROS accumulation in Mitochondria–>Imbalance between Antioxidats/ROS->Oxidative stress ----> Mytochondrial Dysfunction
Increased ROS in the mitochondria will decrease glutathione. This will contribute to a depletion of glutathione.
Methylation blocks will contribute to the person’s inability to replenish glutathione properly in order to go on with the correct metabolism of finasteride.
Finasteride is an inducer of GST pi in the prostate, which means it probably increases ROS and this is a compensatory mechanism. Could be that this happens as well in the liver. If so, it means finasteride increases ROS in the liver.
Increased ROS mitochondria------->Decreased Glutathione
Methylation Blocks------------------>Decreased Glutathione
Finasteride induces ROS-----------.>Decreased Glutathione
Decreased Glutathione----------------------------------------> Depleted glutathione
given enough time leads to
Depleted Glutathione------------>Problems in Krebs Cycle
leads to
A dysfunctional mitochondria cross talks with Endoplasmatic Reticulum and indirectly makes it elevate the generation of ROS. This leads to ER Stress which is involved in thousands of gene changes!!!
A dysfunctional mitochondria will create an accumulation of Carboxy Finasteride.
A high level of Carboxy Finasteride maybe (or finasteride itself???) is the factor that makes high dosage finasteride inhibit 5beta reductase.
5 beta reductase inhibition inhibits Pregnane X receptor. This in turn leads to lowered CYP3A4 expression (maybe this is helpful??)
5 beta reductase inhibition impairs bile acid synthesis.
Glucocorticoid receptor is involved in a cross talk with Pregnane X Receptor. So that dexamethasone is modulating PXR as well as GCR.
High levels of Carboxy Finasteride–>inhibition of 5beta reductase–>inhibition of PXR–>decrease of CYP3A4—>accumulation of finasteride
High levels of Carboxy Finasteride–>inhibition of 5beta reductase–>impaired bile acid synthesis---->impaired bile flow—>high bilirubin
UGT1A3 mutations can also lead to impaired bile flow which lead to high bilirubin.
Could be that a Foxa2 defect is present as well and this will lead to Bile acid homeostasis dysregulation lead to ER Stress.
Bile Acid Problems, Homeostasis Dysregulation ------------------> ER Stress
lead to
Accumulation of finasteride together with CYP2D6 -/-, will lead to higher estrogen. Higher estrogen is associated with cholestasis. Highish concentrations of finasteride in rats, sometimes leads to leydig cell hyperplasia.
ER stress ties in with the Dolichol Deprivation Theory made by TNTW, which in turn ties in with 5AR3 inhibition.
Dolichol Deprivation Theory (due to inhibition of 5AR3??)–>UnfoldedProtein Response problem—>ER Stress
ER Stress leads to Drug Induced Liver Injury. This leads to systemic ROS production and systemic oxidative stress state.
Over time the drug exits the system, and the liver recovers. But maybe somewhere along the above process of damage, some organs were damaged, some genes methylated due to ER stress and/or hormonal changes, and mitochondrias become dysfunctional, leading to a host of problems. The PXR is involved with glucocorticoids as well and maybe this lead to the adrenal problems. I won’t theorize so much more as this is obviously an impossible exercise with such few data. I will perfect this as time goes by. I’m positive liver has had much influence in our condition and I will prove it is dysfunctional upon quitting.
Ideas on how to address this (this is not an advice on what to do! Follow this at your own risk and responsibility if you want):
----> PXR agonist
----> CYP inducer
----> UGT inducer
----> P450scc inducer (still have to check this one out too…forgot)
-----> Foxa2 inducer (impossible, there’s no data in this)
-----> ER stress killer
-----> Increasing Glutathione
-----> Helping dysfunction mytochondria
-----> Helping SOD2
-----> Possibly supporting the gut, pancreas, bile (???), adrenals, thyroid…
How to know if this is working out fine:
anyway, just my contribute. i’m not sure any of this makes any sense. But I will try it out. I hope when my vitamin D3 reaches 80, and my thyroid and cortisol normalise, I will solve my insomnia.
I will now buy supplements/drugs.
The pxr agonism option is very risky, i saw many horror stories with cipro a pxr agonist…worse shit than pfs so really maybe not worth the risk… If you want to try it better check if you have the risk alelle first…
Maybe dexa is a safer option and better as it also acts upon gcr…
Not even sure what to say about this. Either madness or pure genius. Either way, well done. Be nice to have one of the PFS docs look at this and see their thoughts.
Basically my idea is that finasteride made a drug to drug interaction with itself or one of its metabolite through pregnane x receptor inhibition. This interferes with cortisone clearing, glucocorticoid signaling and vitamin D metabolisn among other things.