A demethylating agent might help depending on what the problem is. We just don’t know for sure yet. One issue is that without targeted DNA demethylation, we can’t be sure we are having sufficient effect to turn the suspect gene back on without damaging off-target effects. I think it is too speculative to undergo a treatment of this calibre without having a therapeutic target in sight first. Some people are doing these types of treatments because they were popular for some time in the CFS community and some were seeing relief from treating a suspected lack of methyl donors based on 23andMe data showing that they had lower-functioning copies of methyl-donor producing genes. I got burnt badly last Summer by playing around with methylation supplements simply based on some other PAS patients saying they felt more energetic while taking them. I’m still suffering the effects and regret being that stupid.
We don’t have a problem due to bad genetics though, only a possible increased susceptibility. We were all fine before taking whatever caused this condition to develop in us.
I know this isn’t going to help, but did tour doctor tell you take two serotonin drugs at the same time? Seems like this could generally be dangerous in terms of serotonin syndrome.
I’m no endocrinologist, nor biologist. My background is in Electrical Engineering and systems control, and whilst I understand that many on this forum know considerably more about the potential processes at play here, I wish to bring attention to something which I feel has been overlooked of late.
That is the notion that perhaps our issue isn’t epigenetic, but rather a case of hysteresis of the HPT axis.
The body is a complex system and perhaps Finasteride and it’s cessation forced the body into an extremity wherein it became ‘locked’. Think of it as a valley whereby the HPT axis is operating in an abnormal state of operation. Increasing androgens to some degree may not be enough to push the system out of that state. In fact it could have the negative effect and push it further into the abnormal state.
Perhaps a more detailed understanding of PFS will allow us to realise exactly what needs pushing and in which direction in order to restore the HPT axis to a state of normalcy. I hope that the soon to be released Baylor study will provide illumination as to whether PFS is due to an epigenetic change or not.
if 3a-HSD in PFS patients is low then how you explain decreased DHT and increased 3a-diol in their brain?? the enzyme responsible for DHT > 3a-diol conversion is not 3a-HSD??
You brought up a good point. There are multiple isoforms of 3a-HSD enzymes and some of the 3a-HSDs have been found to favor the oxidative reaction. This really complicates the matter.
Going by blood test results of members of this forum, A-diol G is greatly reduced in PFS patients:
There seems to be a trend of normal DHT levels and low A-diol-G that would indicate a net deficiency of 3a-HSD activity.
Something that was very surprising was Melcagni’s team finding normal levels of A-diol-G
ok, i think i now understand where the incongruence is coming from
allopreg depends on both 5ar and 3a-hsd right?
what happens if we have underactive 5ar in the brain? thp, dhp, allopreg production gets compromised and 3a-HSD senses it needs to work harder to keep homeostasis by reducing DHT
but why do we have underactive 5ar in the brain in the first place??
does it makes sense that when the AR is silenced(hypersensitive) the 5ar is underactive to compensate??
The Melcagni study showed what you say, high 3a-A-diol-G in both plasma and CFS, with a normal level of DHT in plasma and low DHT in CFS
The blood tests of a large number of PFS patients of this forum show a low level of 3a-A-diol-G in plasma, with a normal level of T and DHT in plasma.
It was surprising that these two items seemed to contradict and was probably a quirk somehow
Low 3a-A-diol-G was also the case with myself and a couple other PAS patients. Do you know of any PSSD patients who had 3a-A-diol-G tested?
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You make a good point. On the same token, why would the cell reduce DHT, a neurosteroid in its own right, for the sake of THP or DHP? Is it so unimportant? Also, do THP and DHP exert feedback on their biosynthetic enzymes via GABA receptors, or some other means?
Looking at the graph in the Melcagni paper, the sum of steroidogenic machinery appears to downregulated in the brain judging by CSF of PFS, going back to 3b-HSD’s formation of progesterone and possibly a problem with StAR, TSPO, and p450cc.
does it makes sense that when the AR is silenced(hypersensitive) the 5ar is underactive to compensate??
You would think 5ar-1 would upregulate in the case of silenced AR signal. How about in the case of overexpression from lack of AR autoregulation at a point where it still exerts its normal effect on 5ar-1 activity? It should lead to decreased 5ar activity in this case. Would this be a genomic or non-genomic effect? Is there an androgen response element in the 5ar-1 gene? It is a shame there isn’t more research on the AR’s influence on this pathway, so I can’t answer your question.
Correct me if I’m wrong, because I can’t come up with the reference with short notice and little time. 5-ar is the rate-limiting step in this pathway. It’s not a matter of it being underactive if oxidative 3a-HSD activity is severely shunted and/or reductive activity greatly increased.
Yeah, same. I went off on a few tangents and didn’t have time to find sources for what I was saying.
If I had to guess, I would say blocking the 3a-HSDs wouldn’t accomplish anything except making someone feel much worse. The preceding enzymes should be upregulating already and they aren’t for us for some reason.
