Methylation Block and Androgen Dysfunction (post 1 of 2)
There is no doubt there is a long history of interest in elucidating any androgen insensitivity/dysfunction in PFS. Androgen dysfunction would explain a lot of the symptoms of PFS, and also explain the PFS paradox that some have normal testosterone levels, yet the symptoms of low hypogonadism, and/or lack of response to androgen treatment.
The theory I am supporting in this thread has aligned well with the symptoms observed in groups with a methylation block and with a small number of test results on this forum. In an effort to generate more interest in testing and treatment testing, I will continue to post on what I have found.
I’ve come across a lot of biological reasons why high oxidative stress and a methylation block could lead to general androgen dysfunction. But two are clearly documented/researched ways that high oxidative stress and a halted methylation cycle likely leads to androgen dysfunction. Both are by reducing the effectiveness of Androgen Receptor. I think both of these have a compounded effect. This is one.
Review of this thread
In this thread, I have proposed a theory of PFS:
- Finasteride causes high oxidative stress,
- Which leads to a vicious cycle where the cells stop producing the body’s main antioxidant and the critical methylation cycle stops running. Which means methyl groups are no longer passed around. Which further has major biological consequence.
One consequence of a halted methylation cycle relevant to this post: S-Adenosyl-Methionine (SAMe), which has a job of transferring methyl groups to other molecules (1), is depleted in the Methylation cycle block.
What is Androgen Receptor
Androgen Receptor (AR) is a transcription factor - which means it activates gene expression in androgen sensitive tissues. As we all know, AR is activated by androgens, such as testosterone and DHT, and once activated it stimulates expression of other genes (for a known list of AR targets, see the AR wiki page en.wikipedia.org/wiki/Androgen_receptor).
Simple explanation of the research presented in this post
Methylation of AR (at least) doubles the activity of AR. Methyl-groups are attached to AR via SAMe.
Tying back to this theory: reduced methylation means a weakened AR.
(note that the below research is about methylation of the fully expressed AR protein, not epigenetic methylation of DNA. In this case methylation of the protein means increased activation)
A halted Methylation Cycle causes reduced androgen receptor activity
In the paper ‘Regulation of the androgen receptor by SET9-mediated methylation,’ the authors demonstrate that methylation of androgen receptor causes a 2-fold enhancement in the activation of AR (2). Figure 4c (full paper linked at footnote 2) is a plot of an AR target gene activity (measure of how much AR is binding to a gene):
AR by itself activates gene targets at baseline = 1.
Then AR + DHT activates target genes at 3 times that of baseline.
And AR + DHT + methylation of a specific amino acid further amplifies AR’s activity to 6 times the baseline value.
So, when the methylation cycle is not running, methyl groups are not moving around the biochemistry of the cell, and AR activity is weakened.
In a second paper released independently and published around the same time: ‘Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase’ (3), a second amino acid on AR was found to be methylated, and experiments showed a similar effect. My favorite line from the discussion of this paper: “…methylation bestows AR with enhanced transcriptional activity…”
This paper goes on to further emphasize the importance of SAMe and how the redox state (which we know to be dependent on glutathione levels) influences the activity of AR. Here’s the quote from the discussion:
“Given the overlapping methylation and acetylation site at K630, and dependence of acetyltransferase and methyltransferase on the respective cofactors (acetyl-coenzyme A and SAM), we speculate that competing dynamics between acetylation and methylation of AR at K630 may be guided by redox, metabolic, and nutritional states of cells”
Important notes:
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In both papers they used a radioactive SAMe to show that the methyl group that makes it to AR is originates SAMe. Again, SAMe is depleted and not replenished in the ME block.
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Both papers show that AR is directly methylated, which influences it’s activity. But they both go on to show that methylation does more work at the chromatin and/or promotor regions. I am however keeping this post simple and only talking about direct methylation of AR.
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Both papers show that methylation enhances AR-dependent transactivation by increasing N/C-terminal interactions and recruitment of the receptor to target genes - again, not diving into this for simplicity.
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en.wikipedia.org/wiki/S-Adenosyl_methionine
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Regulation of the androgen receptor by SET9-mediated methylation, nar.oxfordjournals.org/content/e … kq861.full
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Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase, mend.endojournals.org/content/25/3/433.full
