@Dubya_B: Do you know anyone, or any protocole that fixed the pfs typical insomnia: sleeping just a few hours, then waking up fully awake all of a sudden and then turning and tossing the rest of the night, barely sleeping if you can call it sleep ?
It’s a symptom I’d really like to tackle.
Is the question does Fin/Dut become depleted after becoming part of the 5-ar+NaDP+Fin/Dut complex? (not that this is not an important question because it is)
OR is the question did Fin/Dut temporally becoming a part of the 5-ar+NaDP+Fin/Dut complex cause problems with 5AR and other enzymes?
I was not being sarcastic in my response above. I apologize if it came across that way. I’m not familiar with the theory that was floating around a couple of years ago and I’m not arguing against it or in favor of it simply because I don’t know what the theory is. Instead the point that I was attempting to make is that if the molar concentration of Fin/Dut (and 5-AR enzymes) is entirely insignificant compared to the concentration of NaDP+/NaDPH in any given cell why is it that when Fin/Dut becomes a part of the 5-ar+NaDP+Fin/Dut complex (be in temporally or permanently) do we experience such a large reduction in serum DHT concentrations? The point being if this is how Fin/Dut inhibits testosterone-DHT conversion by becoming a part of the 5-ar+NaDP+Fin/Dut complex it’s hard to agree that this is as insignificant as you suggest if its temporally inhibiting DHT to such a large degree.
Are you saying that Fin/Dut becomes a part of the 5-ar+NaDP+Fin/Dut complex and in addition works as a competitive inhibitor of the 5AR enzyme which explains the actual reduction of serum DHT levels while on the drug? If this is the case than why even make Fin/Dut a part of the 5-ar+NaDP+Fin/Dut complex? In other words why did the creators design the drug to become a part of the 5-ar+NaDP+Fin/Dut complex? You appear to have a background in biochemistry so you are probable a good person to ask. Is this the norm for inhibitor based drugs? To become a part of the cofactor? I have no background in this like most people here so all I can do is read on the internet. But upon doing so I cannot find another inhibitor based drug that inhibits it’s target enzyme by becoming a part of the enzymes cofactor. Am I wrong? I am totally open to the real possibility that I am wrong and hope that I am so I can rule this out and move onto the next.
I suffered greatly in this department. In fact, my insomnia was so bad at one point that I stayed up for six weeks. I substantially improved my sleep issues with Glycine, magnesium and the herb ziziphus. However, I progress backwards fast if I stop taking these supplements. I could say that as long as I take these supplements my sleep is about 75 percent pre PFS. I don’t need ziziphus every night. But I need the Glycine and magnesium every night
unless we have a pre disposition to taking anything that binds to something that is at the center of many cell activities. This theory would certainly explain the variety of side effects.
a couple of practical but not so scientific points has me thinking along these lines. I took Dut for a month when I was 22 years old to treat an enlarged prostate. I had no issues on or after Dut. So if my issue is in result of having a genetic pre predisposition to experiencing epigenetic changes in result of taking a 5ar inhibitor my gut feeling tells me that this epigenetic change would have occurred immediately at the time of taking Dut how the syndrome manifest’s for everyone else while on or immediately after stopping the drug. Instead, my issues came four years later after taking saw P. That’s when I got PFS. Then three years after that I took Saw P again and got even worse this time completely crushed. So where I am going with this is that it appears for me this was an accumulative thing each time depleting something vital required for optimal functioning and that the difference between me and most PFS victims is that taking Dut once was not enough to deplete what ever this is to give me problems and for me It took “more”. Of course this theory assumes that Dut/Fin work exactly like Saw P does. I have found evidence that supports this and evidence that debunks Saw P working exactly like Fin/Dut. This theory also assumes that an epigentic change cannot occur as an accumulative thing.
awesome post.
sorry if you already answered this. Did you ever have Allopregnanolone and tetrahydrodeoxycorticosterone tested? I think this line of thinking has a lot of potential
Fin/Dut are irreversible competitive inhibitors of 5-AR. Let’s say that once a particular 5-ar enzyme becomes part of the aforementioned covalently-bonded 5-ar+NaDP+Fin/Dut complex, then it is permanently inert.
For the remainder of its existence, the active site is blocked and it will no longer act as a catalyst in the reaction of T + NaDPH -> DHT + NaDP+ and it will eventually be destroyed by the cell’s waste management systems.
Meanwhile, new 5-ar enzymes are being produced and if fin/dut is present in appreciable concentrations, those new enzymes will share the same fate. If no fin/dut is present, they will catalyze the reaction of T + NaDPH -> DHT + NaDP+
More discussion about the mechanism of action of finasteride here:
Not going to go into a lecture about seeing the forest for the trees, but the result of taking fin or dut is a reduction of DHT and some other products of 5-ar metabolism. Either drug could work by sucking 5-ar into another dimension on a molecule-per-molecule basis and the result would still be the same.
I haven’t because there’s no clear path to enhance the 3a-HSD or 3b-HSD complex. It is my understanding that low Allopregnanolone and tetrahydrodeoxycorticosterone with high cortisol is what prevents us from having good sleep and unless we can fix 3a-HSD and 3b-HSD there’s no point confirming that Allopregnanolone is missing.
It costs hundreds of dollars to have those tested, then maybe some supplements can be taken. It would be dose dependent so from my point of view would fix nothing.
Epigenetic modifications can occur for all kinds of reason: a bad long term abusive relationship, pollution in the air, and yes, the very supplements we’re taking to ease our symptoms. There’s no telling if the epigenome will or will not react.
I took fin for 20 years and started having symptoms after 17 years. If I had stopped 10 years earlier, would I have had pfs ? Hard to tell. Than there are those who got pfs from 1 pill. Clearly, epigenetic damage can occur from taking a pill as well as from stopping taking it.
But to me, this is somewhat irrelevant as long as I can deal with the symptoms. The permanent solution, if there is one, is to change our epigenome so it gets as close to a healthy person as it can and for this, I study and use the suggestions given to increase longevity. It turns out aging is more related to excess epigenetic damage than telomere shortening. Anyway, tricks like fasting, intermittent fasting, being in ketosis etc… produce sirtuins to work on the epigenome AND increase the length of the telomeres.
Already I see signs of epigenetic damage supposed to be permanent clearing out: I’ve had freckles on my face from a bad sunburn 28 years ago and dermatologist told me it was permanent. They are now disappearing ! 75% gone already and those are caused by epigenetic damage. I suppose it’s working on the rest on my body as well.
“Finasteride was originally thought to act as a competitive inhibitor with nanomolar affinity for 5α-reductase type 2 (12). More recently, it was found that finasteride acts as a mechanism-based inactivator of this enzyme”
“Subsequent to inhibitor binding, there is hydride transfer from the NADPH cofactor to the Δ1-2-ene double bond of finasteride”
“The intermediate enolate tautomerizes at the enzyme active site to form a bisubstrate analogue in which dihydrofinasteride is covalently bound to NADP+ The bisubstrate analogue has subnanomolar affinity for 5α-reductase type 2”
“Both AKR1D1 and 5α-reductase type 1 play important roles in the hepatic clearance of steroid hormones, suggesting that high dose finasteride may have an adverse effect on hepatic steroid metabolism”
“Inhibition of AKR1D1 by high dose finasteride would also deprive PXR of its natural 5β-pregnane ligands, resulting in diminished CYP3A4 induction”
“By contrast, in addition to being involved in bile acid biosynthesis, 5β-reductase is responsible for generating 5β-pregnanes, which are natural ligands for the pregnane-X receptor (PXR) in the liver”
“PXR is involved in the induction of CYP3A4, which is responsible for the metabolism of a large proportion of drugs (5, 6). Thus both 5α-reductase and 5β-reductase are involved in the formation of potent ligands for nuclear receptors”
“This could result in significant drug-drug interactions. Importantly, finasteride itself is metabolized by CYP3A4, suggesting that high dose finasteride might prevent its own metabolism (27)”
What if (AND THIS IS JUST A THEORY NOT BEING PRESENTED AS FACT) finasteride prevents it’s own metabolizing at least to a degree and if we had issues with PXR and or CYP3A4 that prevented it’s metabolizing and it’s still binding our NADPH. This is just a thought. And if it’s wrong that does not mean it’s smart to move on and not continue to take a closer look at NADPH
again these are just logical ideas and thoughts that may have been overlooked or not looked at close enough
Intersting thoughts on Epigenetic modifications
I have been looking into the point you made about possible low Allopregnanolone and tetrahydrodeoxycorticosterone with possible high cortisol being responsible for our sleep problems. I am in the middle of doing extensive cortisol testing. So far I have had a middle range normal morning and evening plasma cortisol reading. I have had a normal mid range cortisone reading. I have also had a normal cortisol:cortisone ratio test. This tells me that I am producing the right amounts of cortisol and that proper amounts of my cortisol are converting to cortisone. I will also be doing a multiple time per day saliva cortisol test to get the most detailed confirmation possible that my cortisol levels are remaining stable through out the course of the day. So if everything else comes back normal with my cortisol testing I can logically conclude that if I have an issue with cortisol its at that my GC receptors are either down regulated or up regulated. If this ends up being the case my guess is that I am in low in Allopregnanolone and tetrahydrodeoxycorticosterone which caused the GC receptors to become more sensitive to compensate.
There may be no clear path to increasing 3a-HSD or 3b-HSD but that does not mean there is no path at all. I think that Allopregnanolone and tetrahydrodeoxycorticosterone needs to be tested. I’m taking it that far. I am getting it tested. Hundreds of dollars is worth my life.
Cortisol could be high or normal, but the issue is not cortisol or GC in my opinion. Those have not been affected as, IMO, they are not part of the main 5ar complex fin attacked.
3a-HSD neutralizes DHT. If DHT went lower because of 5ari, I believe the body had to lower 3a-HSD to try and maintain some DHT.
Pregnenenolone + 3b-HSD= Progesterone, + 5ar = 5a-DHP, +3a-HSD = Allopregnanolone.
If you’re to test stuff, test progesterone (should be 0.8ng/ml) and you can either test 3b and 3a-HSD, or their metabolite 5a-DHP and Allopregnanolone as the metabolite is more exactly what you want and they indicate if the precursors are working correctly.
If you don’t mind, tell me your results !
ZRTLab.com can do those. If you do it with them, please tell me how much they charge !
I agree with everything you said. The fact that my recent cortisol and cortisone results show that I have proper amounts of active cortisol converting to inactive cortisone confirms that my 11-Beta-Hydroxy Steroid dehydrogenase (11B-HSD) enzymes are working properly. This is important to confirm because your active cortisol could be in proper amounts in plasma but if not enough of it is converting to inactive cortisone this could result in too much cortisol binding to the mineral corticoid receptors brining on similar symptoms that we experience. So ruling this out is good and I did rule this out.
My recent PROGESTERONE tested in @: <0.5 <1.4 ng/mL
So my recent 0.5 Progesterone result is close to your 0.8 Mark. This suggests that my 3B-HSD enzymes are working properly. However, my 3B-Androstanediol (3B-diol) tested in @ below lab reference range low in 2013. Low 3B-diol suggests that my 3B-HSD enzymes are not working correctly because 3B-HSD also converts DHT to 3B-diol. BUT additionally 17B-hydroxysteriod dehydrogenases (17B-HSD) also convert’s DHEA to 3B-diol. So with this being said my low 3B-diol readings may be in result of 17B-hydroxysteriod dehydrogenases (17B-HSD) not working correctly, which, is suggested by the fact that it appears 3B-HSD, is able to convert proper amounts of Pregnenenolone to Progesterone via 3B-HSD.
There is also the possibility that 5AR recovered enough or was not effected enough in certain places to be able to convert proper over all amounts of T-DHT but not in other places where conversion of progesterone into 5a-DHP takes place. Following this logic there is also a possibility that 3a-HSD could be working well enough in certain areas to be able to covert DHT to 3a-diol but not well enough to convert 5a-DHP into Allopregnanolone. Also enzymes such as 3a-Hydroxysteriod dehydrogenase (3a-HSD) can also convert 3a-diol back into DHT and compensate by doing just this when 5AR is no longer working properly. So after really digging into this it becomes clear that the only way for each individual to know their status on each one of these parameters is to get tested for everyone one of them or as many of them as possible including 5a-DHP and Allopregnanolone like you said.
I am looking into as many labs and companies as possible to try to find the best place to have these tested at the best price. I will let you know.
Yes. Please let me know. Your insights are intetesting.
Do you mind sharing the sites you’re investigating for the testing, either here or through PM
This is all interesting and something I’ve also tried to figure out in the past few moths. Here is my recent 24h Cortisol test results for comparing. This was done trough Dutch Adrenal test which was measured from urine, my former test was done trough saliva ->
So basicly my 24h Cortisone curve is quite optimal and its making the spike on the mornings but the conversion to Cortisol doesnt work at all. The morning spike is lacking and Cortisol is very low overall througout the day.
But how do we even know if these test results are accurate?
I PM’d you on what I have been looking into.
There is no more reason to question ZRT’s accuracy compared to quest diagnostics or lab corp.
The issue with ZRT is that they refuse to sell the LCMS saliva test kit directly to us. They want us to go through providers that they have partnerships with and request through their providers to order us the kit. The bad thing about this is now we need to deal with money hungry functional health doctors that want to scam us and charge us “to go over the results with us” who know less about allopregnanolone than we do
We just need to be able to buy the kit directly from ZRT labs. I suggest that you call and ask them if you can buy their LCMS saliva test and refuse to go through their “linked” providers to get the test. Show them that there is a demand for their LCMS saliva test kit but that we want to buy it directly from them like they sell many of their kits directly to individuals. The point to get across to ZRT is that we have already been through enough nonsense so the last thing we want to deal with is one of their providers who want us to pay out of pocket for “their medical services”.
sounds good.
I am getting ZRT labs LCMS Saliva steroid profile kit done. It will test for allopregnanolone. The problem is that ZRT labs requires you to go through one of their providers to order the LCMS Saliva steroid profile kit which is undesirable. They are functional health doctors who get the LCMS test kit from ZRT for cheep and price gouge us. The provider that i got mine through made $300 plus off the sale of one kit to me and wants to charge me more to “let me have my results”
ZRT’s concern is that if they sell us the LCMS kit directly they will feel obligated to help us. I attempted to explain to them that people in this community have already been let down by the medical establishment so the last thing we are going to do is call ZRT for “help”
Say we test for low ALLO and THDOC, what would be an actionable response?
The actionable responses:
Learn more about which metabolites/neurosteroids were or were not affected
Learn more about whether or not different metabolites are affected differently in different PFS victims. You could be low in ALLO and or THDOC and I may not be
Having the opportunity to narrow in on what has been affected in my case. In 2013 I was low in 3b-diol. So having had the opportunity to learn that 3b-diol acts as a potent agonist of the estrogen receptor allows me to possibly make a connection with the fact that I also get worse from taking an estrogen Aromatase inhibitor. This can help me explore a possible path to recover. Maybe I’m deprived of estrogen which would certainly be something that I would have never have considered if I did not know that at least at one time I was low in 3b-diol. Maybe even figuring out that being low in 3b-diol may be a sign that you are a PFS vicim who will get worse from taking an aromatase inhibitor. This forum had a guy once who killed him self after taking an aromatase inhibitor while others get some results or at least not worse from taking an aromatase inhibitor. So potentially having a "maker’ to go by to know if you are someone who should or should not take an aromatase inhibitor would be helpful to say the least.
Taking metabolites/neurosteroids that we are personally low in and researching which enzymes are responsible for metabolizing it providing a clue as to which enzymes were affected. Researching if that enzyme uses the same co factor that Fin, Dut and possibly Saw P binds in order to see if this is a path that leads to anything
Supplementing what we are low in. If I am low in ALLO I am going to do what ever I need to do to get my hands on ALLO and take it. I will not assume that because
5a-DHP which concerts to ALLO did not cure me that taking ALLO would not cure me. But I’m certainly not going to go through what ever trouble that I would need to go through to obtain ALLO and take it if I don’t even know if I am low in it.
If I am low in THDOC I’m going to use every resource available to me to research THODC and the possible implications with not having enough of it.
Use the results to create awareness. Bring the results to my doctor’s attention to further the cause of this forum
Give the results to a lawyer to help initiate a case
In other words, anything I can do with the results will be my actionable response
