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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.
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.
Isotretinoin can also 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 its possible that Isotretinoin has similar side effects to PFS
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
"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.
so we can fix either:
1. NADH and NADPH ratio: NAD to NADH ratio include niacinamide, methylene blue, inosine, and quinones such as thymoquinone, beta-lapachone, vitamin K (MK-4), etc.
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
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
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.
Isotretinoin can also 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 its possible that Isotretinoin has similar side effects to PFS
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
"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.
so we can fix either:
1. NADH and NADPH ratio: NAD to NADH ratio include niacinamide, methylene blue, inosine, and quinones such as thymoquinone, beta-lapachone, vitamin K (MK-4), etc.
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
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
