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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.
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.
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
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.
