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PFS: 3a and 3b-HSD theory

Hans

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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.

"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.
 

Mauritio

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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.
So 5a reductase 1 is responsible for an increase in allopregnanolone and 5a reductase 2 for DHT ?
 

Hans

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Do you think this applies to post accutane?
What are your main symptoms?
Isotretinoin increase FoxO3 which increase FoxO1, which inhibits LXR. LXR increases 3a-HSD and represses 3β-HSD, so that would mean that when Accutane inhibits LXR, the activity of 3a-HSD would be less and 3b-HSD be more. So it's possible.
 

Hans

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Yes , especially since it also boosts 3bHSD ,which seems unfavorable for PFS .
But experience trumps theory so , I would advise everybody to give it a try .
This is mainly just a theory, with nothing being conclusive since we can't test allo or isopregnanolone levels in the brain.
 

Mauritio

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Mostly, yes.
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
This is mainly just a theory, with nothing being conclusive since we can't test allo or isopregnanolone levels in the brain.
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 .
 

Hans

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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
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.
 

Jayvee

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Thanks Hans! From a supplement/diet perspective would their be anything safe to start out with improve the NAD:NADH ratio, I have fairly good energy from Pau D’arco but it seems to negatively effect sleep (could be reacting with something else in my diet). Also Vitamin K can have similar negative effects and make me have this weird agitated feeling. Gelatine and TUDCA are the only thing that have been consistent in improving symptoms and I have found the same with other sufferers.
 

GenericName86

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I'm not really knowledgeable enough to really help with this thread but I'm glad you went ahead and made this a topic @Hans looking forward to seeing the discussions that hopefully come from this.

Sorry if not understanding this correctly but In regards to 3a-hsd, if it's not functioning correctly is there any way to help it directly or is the only option to help correct the NADPH/NADH Issue?
 
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What are your main symptoms?
Isotretinoin increase FoxO3 which increase FoxO1, which inhibits LXR. LXR increases 3a-HSD and represses 3β-HSD, so that would mean that when Accutane inhibits LXR, the activity of 3a-HSD would be less and 3b-HSD be more. So it's possible.
The only remaining symptoms would be insomnia and bone cracking. The severe depression went away.
 

Hans

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Thanks Hans! From a supplement/diet perspective would their be anything safe to start out with improve the NAD:NADH ratio, I have fairly good energy from Pau D’arco but it seems to negatively effect sleep (could be reacting with something else in my diet). Also Vitamin K can have similar negative effects and make me have this weird agitated feeling. Gelatine and TUDCA are the only thing that have been consistent in improving symptoms and I have found the same with other sufferers.
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?
 

Hans

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I'm not really knowledgeable enough to really help with this thread but I'm glad you went ahead and made this a topic @Hans looking forward to seeing the discussions that hopefully come from this.

Sorry if not understanding this correctly but In regards to 3a-hsd, if it's not functioning correctly is there any way to help it directly or is the only option to help correct the NADPH/NADH Issue?
NADH and NADPH are only the cofactors. These enzymes can also be regulated by other processes or enzymes in the body, such as LXR for example.

Here is a summary of things that can modulate these enzymes that I have collected so far.

3a-HSD
Sulforaphane increases 3a-HSD (R)
Cortisol enhances 3a-HSD in adipose tissue (R)
Fat tissue expresses 3a-HSD (R)
dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3α-HSD in the oxidative direction (conversion of 3α,5α-tetrahydroprogesterone to 5α-dihydroprogesterone). 5α-DHP is further reduced to 3α,5α-THP by the 3α-hydroxysteroid dehydrogenase (3α-HSD), which controls the amount of 3α,5α-THP in the brain
Increased by Nrf2 (R)
Nicotine and cotinine inhibit it (R)

3b-HSD
DHT -> 3bHSD (NADH) -> 3b diol
Prolactin (R)
PRL activates Stat5 regulation of the human HSD3B2 promoter (R). GH increases STAT5 (F)
HCG (R)
angiotensin II
Cortisol stimulates whereas androgens inhibit
Insulin, IL-4 and IGF-1 induce type 1
insulin and IGF-I increased 3β-HSD
Progesterone increases it
terbutaline and isoproterenol (β-adrenergic agonists) produced dose-dependent increases in 3β-HSD mRNA in porcine granulosa cells
Estradiol decrease it
PGF2α reduces it
Opioids inhibit it
NO suppresses it
Spearmint, raw potato diet, chickory suppress it (R, R)
Isoflavonoids and mycotoxins (R) increase it
PUFA diet lowers it whereas saturated fat and MUFAs increase it (R)
Coconut oil, zinc, T3, retinoic acid also upregulate 3-beta-HSD
 

Jayvee

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I have the Pau’darco in tea form so difficult to gage the dose. I tend to have it late morning to try limit it effecting sleep but so far not been able to properly mitigate its negative effect on sleep (it could be something else but that seemed to be the only change I was making When having poor sleep).

I’ve not tried Lapodin but due to do an order so might give it a try.

I was taking Q10 for a while and having some really good effects (some days even felt cured but that didn’t last long and seemed to stop working as well).

With this theory, is the overall goal to increase 3a-HsD and lower 3b-HSD or am I misunderstanding that?
 

Hans

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I have the Pau’darco in tea form so difficult to gage the dose. I tend to have it late morning to try limit it effecting sleep but so far not been able to properly mitigate its negative effect on sleep (it could be something else but that seemed to be the only change I was making When having poor sleep).

I’ve not tried Lapodin but due to do an order so might give it a try.

I was taking Q10 for a while and having some really good effects (some days even felt cured but that didn’t last long and seemed to stop working as well).

With this theory, is the overall goal to increase 3a-HsD and lower 3b-HSD or am I misunderstanding that?
Have you tried PQQ before?
Yes, increase 3a-HSD to increase allopregnanolone (GABA agonist) and lower 3b-HSD to lower isopregnanolone (GABA antagonist).
 

Jayvee

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Have you tried PQQ before?
Yes, increase 3a-HSD to increase allopregnanolone (GABA agonist) and lower 3b-HSD to lower isopregnanolone (GABA antagonist).
No, never even heard of that. Just had to google it. Could it stack well with Lapodin?

thank you! You have no idea how much this Information helps people.
 

Hans

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No, never even heard of that. Just had to google it. Could it stack well with Lapodin?

thank you! You have no idea how much this Information helps people.
It can definitely stack well with Lapodin. It's great against excess glutamate and lactate. But since you're getting results from gelatin, perhaps you rather benefit from NMDA agonist (glycine is an agonist). Piracetam, tianeptine, serine and sarcosine can also promote/restore the glutamate system.
 

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