PFS: 3a and 3b-HSD theory

[Hans]

You mean taking DHT cream?

Any carrier for DHT should work.

 

[sladerunner69]

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

Do you ever feel like progesterone is weakenning your androgens? I feel more relaxed and pleasant with progesterone, but it aso makes me sedated and unmotivated. I guess it is best taken with androgens like androsterone and dhea. However, when I combine these two pwoerful anti-estrogen substances I feel I am lowerring estrogen too much which seems to supress my emotions/feelings and lowers my libido.

 

[Alex Jaramillo]

Do you ever feel like progesterone is weakenning your androgens? I feel more relaxed and pleasant with progesterone, but it aso makes me sedated and unmotivated. I guess it is best taken with androgens like androsterone and dhea. However, when I combine these two pwoerful anti-estrogen substances I feel I am lowerring estrogen too much which seems to supress my emotions/feelings and lowers my libido.

No, I do feel more relaxed and pleasant with progesterone. It stimulates my appetitite, improves my mood, libido and sleep. It does make me eat more though

 

[Drareg]

Okay thanks, interesting! Cistanche increases 5a reductase 2 , 12 fold ,but lowers type 1 about 40% IIRC , so it might be wise to take a little 5adhp with it or something else that increases allopregnanolone

Yes I figured. That's why said it'd advise everybody to try it out themselves as there's so many possibilities a supplement can affect you .

Do have any studies on cistanche doing this?
There seems to be little to no research on 5-AR type 2 outside of prostate issues, the structure was only found last year I believe, most of the studies are about inhibiting it, nothing I can find about increasing it.

 

[GenericName86]

Do have any studies on cistanche doing this?
There seems to be little to no research on 5-AR type 2 outside of prostate issues, the structure was only found last year I believe, most of the studies are about inhibiting it, nothing I can find about increasing it.

Cistanche increases steroidogenic enzymes, lowers NO, helps osteoporosis and Alzheimer's

Study there mentions 5-ar type 2.

 

[Mauritio]

Do have any studies on cistanche doing this?
There seems to be little to no research on 5-AR type 2 outside of prostate issues, the structure was only found last year I believe, most of the studies are about inhibiting it, nothing I can find about increasing it.

Post in thread 'Cistanche increases steroidogenic enzymes, lowers NO, helps osteoporosis and Alzheimer's' Cistanche increases steroidogenic enzymes, lowers NO, helps osteoporosis and Alzheimer's

 

[Drareg]

@GenericName86 @Mauritio Thanks , nobody seems to talk about it much, not even in bodybuilding forums, I would start a separate thread but there is little info to post on it.

 

[Mauritio]

@GenericName86 @Mauritio Thanks , nobody seems to talk about it much, not even in bodybuilding forums, I would start a separate thread but there is little info to post on it.

Yes I think there should be more talk about expression of certain types of 5 alpaha reductase in certain tissues and what consequences that has .

 

[outcast1979]

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.

Late reply but i have stumbled upon a post lately from a guy who had pssd and cured by using
C60 Olive Oil witch is a known electron acceptor,so your theory could be right.

 

[LeeLemonoil]

Posted here yet?

Age-related steroid deficiency may be treatable with niacinamide

The study is actually about eye health, and the effects androgens play in it. However, the findings are not limited to the eyes and are in fact applicable for any other tissue/organ experiencing a decline in steroidogenesis with advancing age, which is basically all of them. As such, I am...

raypeatforum.com

 

[edoos]

@Hans Would it be good to try GABA supplements for ppl suffering from anxiety and Insomnia and then if it works switch the precursor as you said?

 

[Hans]

@Hans Would it be good to try GABA supplements for ppl suffering from anxiety and Insomnia and then if it works switch the precursor as you said?

Maybe yes, but glycine is more effective at increasing brain gaba than gaba itself. Insomnia and anxiety can also be caused by excess noradrenaline and/or adrenaline. A few people with PFS told me that they do much better on a low histamine diet. So perhaps their methylation is screwed, leading to the buildup of noradrenaline and histamine.

 

[edoos]

Maybe yes, but glycine is more effective at increasing brain gaba than gaba itself. Insomnia and anxiety can also be caused by excess noradrenaline and/or adrenaline. A few people with PFS told me that they do much better on a low histamine diet. So perhaps their methylation is screwed, leading to the buildup of noradrenaline and histamine.

That's interesting cause my issues since PFS is being stressed out in no time form normal life stimuli. I think the PNMT enzyme has a role here, it maybe de not rebound correctly. I'm currently on beta blocker and small dose of bromazepam because adrenaline shoot during normal life situation was giving me heart rythm trouble. For example my body can't cope with a normal workout it stress ou to a point it trigger a tachychardia.

 

[Tidal]

I won't pretend to completely understand what is being discussed as I find it all very complex. I have anhedonia/depersonalisation from taking antidepressants and recently found my progesterone metabolites were high along with 5a dht and androstenedione.

I've took 5a dhp in the past which did nothing. Does this indicate my allopregnanolone is high?

I've read that ADs impact 3a hsd but i find it all too confusing to understand. I've tried cistanche before which is the only thing that allowed me to catch a cold which is big, because I can't catch colds or get sick now. But no effect on anhedonia/DP

 

[Mister]

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.

Interestingly you talking about nicotinamide for PFS.


I know one recovery with nicotinamide riboside: Experience with and thoughts on Nad+ and hair loss interventions - NAD+

And someone else I know from whatsapp who also had strong improvements and is basically cured.

Vigorious Steve from youtube also says NMN optimizes the 5a enzyme.

 

[GenericName86]

Interestingly you talking about nicotinamide for PFS.


I know one recovery with nicotinamide riboside: Experience with and thoughts on Nad+ and hair loss interventions - NAD+

And someone else I know from whatsapp who also had strong improvements and is basically cured.

Vigorious Steve from youtube also says NMN optimizes the 5a enzyme.

I used NR for a quite a bit a year or so back, noticed some good effects, certainly had some androgenic effects (increased forearm and leg hair) but also noticed my hair and scalp felt better which I mentioned at the time I posted about it I believe, have since stopped using it though. I haven't tried nmn on it's own but I did try alive by science sub NMN but it had tmg with it and I didn't like it all that much, I think they now sell nmn without the tmg now.

 

[Mister]

I used NR for a quite a bit a year or so back, noticed some good effects, certainly had some androgenic effects (increased forearm and leg hair) but also noticed my hair and scalp felt better which I mentioned at the time I posted about it I believe, have since stopped using it though. I haven't tried nmn on it's own but I did try alive by science sub NMN but it had tmg with it and I didn't like it all that much, I think they now sell nmn without the tmg now.

What are you going to try now?