PFS: 3a and 3b-HSD theory

[Hans]

Hey man if Cistanche can lower allopregnanolone and someone wants this herb benefits without messing hormones up, it would be wise to take
Kami-shoyo-san with it, which seem to raise allopregnanolone ? Both seem to go well together wdyt btw i dont suffer from PSSD, i just one the mental benefits from this herb.

You can try Cistanche and if it give you certain negative effects, then no need to add in anything else. If you do get negative that you would relate to low allopregnanolone, then you can add Kami-shoyo-san.

 

[sladerunner69]

Have you tried cortinon?

Have you tried cortinon?

No but I have been using progesterone and dhea on/off, together or seperately, for years.

Dhea gives me a great boost in energy, drive and libido but the issue I used to always enocunter with DHEA is that it gave me an inense irritability preventing me from being able to study or do cognitive work effectively. Lately this hasn't happened nearly as severely as when I first took it several years ago, so it is a good sign my response to dhea is improving. Progesterone seems to have the inverse effect, helping my cognition nad giving me a relaxed pleasant feeling, but leaving me sedated, less motivated and often with little to no libido. I think combing them is a good idea, so I may give that another shot tomorrow. I also think trying the reduced forms of these substances as in 5a-dhp and androsterone, is something to try as I have had some very good effects from both of those individually, though eventually they tend to lower my estrogen too much. When I was taking a lot of androsterone last year I would feel very stiff, unemotional and lifeless, and then drink a small glass of beer and feel significantly better for hours and have some libido return to me.

I would like to try real DHT rather than androsterone, because androsterone apparently has unique anti-estrogen effect that is about 10x stronger than DHT, which might explain why some guys do not like it. Likewise, trying real Allopregnenelone rather than 5a-dhp would be interesting. But that is unlikely to happen anytime soon.

 

[sladerunner69]

Hey man what doses of progesterone have you tried? I still haven’t tried progesterone and no idea how to dose for PFS (if different).

The most straight progesterone I have used is probably 5 drops of progestene which is <10mg. I will notice the effects of 1 or 2 drops fairly quickly, so you don't need much. I also find it quite sedative, I'm not sure if it is because it lowers androgens (I don't think it does) or because it opposed cortisol (I am thinking more and more like this is the case).

 

[Jayvee]

The most straight progesterone I have used is probably 5 drops of progestene which is <10mg. I will notice the effects of 1 or 2 drops fairly quickly, so you don't need much. I also find it quite sedative, I'm not sure if it is because it lowers androgens (I don't think it does) or because it opposed cortisol (I am thinking more and more like this is the case).

thanks man. I might experiment with Progesterone, I could do with some help with getting good sleep and relaxing the kind, maybe smaller doses could be better.

I have been eyeing up some pure DHT (Stanalone) but it’s really expensive. I think it could be good to have in small cyclical doses. Not sure how a pfs person would respond to it. I know of some people who have recovered from the less desirable forms of DHT in some kind of rebound way where they feel like crap for a while then suddenly recover (which throws all my theories out the window).

 

[Alex Jaramillo]

I used 5 alpha dihydroprogesterone for the first time last night at 5 mgs and what I experienced was increased focus, not irritable like I usually am and music sounded a little better, also I felt that I was less judgemental of others.

 

[Jayvee]

I used 5 alpha dihydroprogesterone for the first time last night at 5 mgs and what I experienced was increased focus, not irritable like I usually am and music sounded a little better, also I felt that I was less judgemental of others.

Do you have a source for that? I wonder if this could be useful for pfs. Do you find your sleep improves from it?

 

[Alex Jaramillo]

Do you have a source for that? I wonder if this could be useful for pfs. Do you find your sleep improves from it?

Yes, idealabs. I can’t tell a difference with sleep yet. Progesterone improved my sleep the times i’ve used it. I have about 47 more days left on the 5 alpha dhp though at a 5mg dosage.

 

[Ismail]

My favorite combo for increasing the NAD to NADH ratio include niacinamide, methylene blue, inosine, and quinones such as thymoquinone, beta-lapachone, vitamin K (MK-4), etc.
But ofc it's best to avoid anything that makes you feel worse for the time being. How much Pau d'arco do you take and at what time? Have you tried sublingual Lapodin?

Are you getting your thymoquinone from black seed by any chance? If so, how much do you take? Thanks ?

 

[Ismail]

If someone has too much isopregnanolone, then lowering type I might actually be helpful as it will lower isopregnanolone, but also allopregnanolone. Someone has speculated the people with PSSD might have too much allopregnanolone, so perhaps it's worth a shot trying cistanche for that as well.

@Lukso has good experience with cistanche and he suffers/suffered from PSSD if I’m not mistaken - would be interesting to see his thoughts etc

 

[sladerunner69]

thanks man. I might experiment with Progesterone, I could do with some help with getting good sleep and relaxing the kind, maybe smaller doses could be better.

I have been eyeing up some pure DHT (Stanalone) but it’s really expensive. I think it could be good to have in small cyclical doses. Not sure how a pfs person would respond to it. I know of some people who have recovered from the less desirable forms of DHT in some kind of rebound way where they feel like crap for a while then suddenly recover (which throws all my theories out the window).

Back when haidut could still sell 7keto- DHT I responded very well to it. The first time I took it was amazing. After a few days the effects became less pronounced and then I began to feel very tired and achy when I took it which I now recognize as being a combination of low estrogen and high GABA. I have read those reports too, many times. Generally it is with cycles of androsterone, they will feel bad on it or not feel much of anything, but when they come off it again there is some kind of "rebound" or "snapback" effect where their hormones get moved to a better baseline. I think it may have to do with the baseline DHT improving.

 

[Jayvee]

Back when haidut could still sell 7keto- DHT I responded very well to it. The first time I took it was amazing. After a few days the effects became less pronounced and then I began to feel very tired and achy when I took it which I now recognize as being a combination of low estrogen and high GABA. I have read those reports too, many times. Generally it is with cycles of androsterone, they will feel bad on it or not feel much of anything, but when they come off it again there is some kind of "rebound" or "snapback" effect where their hormones get moved to a better baseline. I think it may have to do with the baseline DHT improving.

I’ve had rebound effects from a few different things, Cyproheptadine makes me feel awful and not human but then I get 2 days of feeling pretty good after. PFS is strange. Never seen it suggested or done but could topical DHT on the scalp have any effect or is that stupid? If DHT has a pro- 5ar effects and all the cascading positives of that, I have found topical T3 on the scalp to do something (could be a psychological effect though).

 

[Alex Jaramillo]

Both progesterone and andro have potent pro-GABA effects, but they obviously have many other benefits as well. Keep us posted man.

So i’ve tried 5a-dhp a few times now in varying doses. 5 mgs, 10, 15, 20 and 30 mgs and it seems I only “felt” it on the very first day at 5 mgs but upon trying that dose again; I did not feel much. All the dosing was oral besides once topically, which I also didn’t feel much. Prog and andro seem to be the golden nuggets for me.

 

[sladerunner69]

I’ve had rebound effects from a few different things, Cyproheptadine makes me feel awful and not human but then I get 2 days of feeling pretty good after. PFS is strange. Never seen it suggested or done but could topical DHT on the scalp have any effect or is that stupid? If DHT has a pro- 5ar effects and all the cascading positives of that, I have found topical T3 on the scalp to do something (could be a psychological effect though).

The problem seems to be that things which increase DHT lower allopregnenelone and vice versa. When I take a lot fo nicotine (big DHT boost) I feel physically awesome and very strong and energetic, but my ability to concentrate goes to hell and I get anxious. Conversely, when I take a bunch of progesterone, gelsenium, 5adhp etc I get relaxed, focussed and can think well but am tired and sedated. There needs to be a way to increase both on balance.

So i’ve tried 5a-dhp a few times now in varying doses. 5 mgs, 10, 15, 20 and 30 mgs and it seems I only “felt” it on the very first day at 5 mgs but upon trying that dose again; I did not feel much. All the dosing was oral besides once topically, which I also didn’t feel much. Prog and andro seem to be the golden nuggets for me.

Yes I recall the effects of 5a-dhp diminishing very rapidly, and have heard others say the same. It is unfortunate because the first time I took 5a-dhp I felt amazing and thought I may have found the elusive "cure"

 

[Alex Jaramillo]

The problem seems to be that things which increase DHT lower allopregnenelone and vice versa. When I take a lot fo nicotine (big DHT boost) I feel physically awesome and very strong and energetic, but my ability to concentrate goes to hell and I get anxious. Conversely, when I take a bunch of progesterone, gelsenium, 5adhp etc I get relaxed, focussed and can think well but am tired and sedated. There needs to be a way to increase both on balance.


Yes I recall the effects of 5a-dhp diminishing very rapidly, and have heard others say the same. It is unfortunate because the first time I took 5a-dhp I felt amazing and thought I may have found the elusive "cure"

Im with you on 5a-dhp but progesterone and andro’s effects stay consistent for me.

 

[edoos]

In this Friday's newsletter, I postulated the theory that it might not necessarily be the 5-AR type 1 or 2 enzymes that are defective, but rather 3a and 3b-HSD.
I quote from the newsletter:

"Most people think that PFS is caused by downregulated 5AR, but a lot of people actually have normal DHT levels a few weeks after stopping finasteride or other 5-AR inhibitors. This indicates that their 5AR type 2 is working. So they speculate that their 5AR type 1 is broken. But if they supplement 5a-DHP, thus skipping the 5AR type 1 enzyme, they still don't resolve their issues.

If you look further, 5a-DHP can be converted to allopregnanolone by 3a-HSD. Allopregnanolone is good since it is pro-GABA and GABA-A receptor activation and promotes the release of GnRH (which stimulates steroidogenesis). Most people with PFS also have anxiety, poor sleep, etc., which is actually a sign of low GABA.
The problem comes in with the production of Isopregnanolone through 3b-HSD, which is a GABA antagonist.
3a HSD uses NADPH as a cofactor and 3b-HSD uses NADH as a cofactor. The enzyme NNT in the mitochondrial membrane converts NADH into NADPH. So if the cell doesn't work very well anymore, then ANT is downregulated and the NADH to NADPH ratio is increased.

So the goal is to decrease NADH (fix complex I of the ETC) and increase NADPH (which enhances mitochondrial function as well as the pentose phosphate pathway)."

Six different NADPH-producing pathways are present in mitochondria: (i) NADP+ transhydrogenation by nicotinamide nucleotide transhydrogenase (NNT) using NADH as a cofactor; (ii) glutamate conversion to α-ketoglutarate by glutamate dehydrogenase 1 (GDH1); (iii) NADH phosphorylation by mitochondrial NAD kinase (NADK2); (iv) isocitrate dehydrogenase 2 (IDH2); (v) malic enzymes (ME2/3); and (vi) the mitochondrial folate cycle.

I speculate that it's mostly related to NNT, more than any of the others, since NNT can contribute up to 50% of total NADPH.

The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP[+] at the expense of NADH oxidation and H[+] movement down the electrochemical potential across the inner mitochondrial membrane, establishing an NADPH/NADP[+] ratio ...

www.ncbi.nlm.nih.gov

"It has often been stated in the literature that NNT has approximately a 50% contribution to the total NADPH flux in the mitochondrial matrix and that the other 50% includes contributions from IDH2 and NADP-MEs"

Another reason why I think it might be NNT related is that when a cell becomes damaged, NNT levels will drop. Improving cellular function should help to increase NNT and NADPH synthesis.

Things that lower NADH include quinones, methylene blue and other electron acceptors. The NAD:NADH ratio can be check by the lactate:pyruvate ratio (which is 10:1 under normal conditions)
NADPH synthesis requires vitamin B1 and B3. NADPH is also a cofactor for 5AR, so increase NADPH, can increase DHT and allopregnanolone.

This could not only be related to PFS, but to other issues as well, such as PSSD.
After getting some positive feedback on my newsletter I decided to post it here as well so that others can also chime in so we can all have a discussion on this.
@sladerunner69 et al.

Thanks for your good work. I think this paper could help to bring some context to it Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism.

I still suffer from bad anxiety, insomnia since more than 10y now. Who have been unfortunately exacerbated since I retry topical fin in 2016 (who was a big mistake). Since then my anxiety and insomnia is difficult to manage. I didn't try yet 5a-DHP because I'm a bit afraid as is a lab molecule, and we don't know yet the side effect profile.

 

[edoos]

If someone has too much isopregnanolone, then lowering type I might actually be helpful as it will lower isopregnanolone, but also allopregnanolone. Someone has speculated the people with PSSD might have too much allopregnanolone, so perhaps it's worth a shot trying cistanche for that as well.

Can you have too much allopregnanolone if your serum DHT is still in the low range after quitting fin? My serum DHT came back at 0,32 ng/ml. So I assume my 5ar2 is ****** and the gene is methylated.

 

[Jayvee]

The problem seems to be that things which increase DHT lower allopregnenelone and vice versa. When I take a lot fo nicotine (big DHT boost) I feel physically awesome and very strong and energetic, but my ability to concentrate goes to hell and I get anxious. Conversely, when I take a bunch of progesterone, gelsenium, 5adhp etc I get relaxed, focussed and can think well but am tired and sedated. There needs to be a way to increase both on balance.


Yes I recall the effects of 5a-dhp diminishing very rapidly, and have heard others say the same. It is unfortunate because the first time I took 5a-dhp I felt amazing and thought I may have found the elusive "cure"

That definitely matches my experience with pro DHT things and pro Allo things. Have you ever tried doing them at the same time as a stack? Ando, DHT and 5a-DHP? Or something to this effect.

 

[Mauritio]

Alterations of gut microbiota composition in post-finasteride patients: a pilot study - Journal of Endocrinological Investigation

Purpose Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual...

link.springer.com

 

[Hans]

Can you have too much allopregnanolone if your serum DHT is still in the low range after quitting fin? My serum DHT came back at 0,32 ng/ml. So I assume my 5ar2 is ****** and the gene is methylated.

Maybe, it's hard to tell as it's impossible to check allopregnanolone levels other than with a biopsy. So combining a little 5a-DHP with DHT might be a good experiment.

 

[edoos]

Maybe, it's hard to tell as it's impossible to check allopregnanolone levels other than with a biopsy. So combining a little 5a-DHP with DHT might be a good experiment.

You mean taking DHT cream?