Methylation of SRD5A2 causing PFS

General Discussion
#1

“The gene SRD5A2 may be tissue specific and not centralised to one single gene that controls expression.” This would explain the vast array in symptoms between PFS patients. When Melcangi checked the cerebral spinal fluid in PFS patients more than half 56.3% showed methylation of the SRD5A2 against controls this is a substantial difference with the unmethylated controls showing higher pregnenolone, dihydrotestosterone and dihydroprogesterone production compared to PFS patients with the methylated SRD5A2 gene. This to me shows a very clear connection that methylation of this gene has an impact on production of key hormones and may be the central cause of Post Finasteride Syndrome. The reason why other PFS patients didn’t show methylation of the SRD5A2 gene in the CSF is simply because Post Finasteride Syndrome is a site specific disease as SRD5A2 is locally expressed in key tissues and not coming from one single gene. It would have been interesting to compare the differences in symptoms between these patients with PFS and methylation in the CSF.

The first sites I believe to get hit by Post Finasteride Syndrome is the prostate, penile tissue and brain as these sites contain the highest concentration of DHT. The genetic predisposition for me will always come down to how much locally acting DHT was being produced in tissues the higher the amount the more predisposed you become. I’m also of the belief that individuals who have been exposed to some anti androgen in the past makes them more susceptible to PFS whether this was taking an antidepressant, shampoo containing anti androgen compounds or some other medication or supplement making tissues more primed for PFS. I’m also of the belief that the reason why people may see an improvement over time is that the methylation of these tissues may decrease as we age but obviously isn’t the case for everyone.

If professor Melcangi had of taken a skin biopsy of the penile tissue in patients with PFS who complained of sexual dysfunction I’m sure that he’d find 80% plus methylation of the SRD5A2 gene.

#2

by Axo

Hi @lakehouse. No, the basic proposal of the publication is in the abstract. It is not plausible to suggest 5ar2’s methylation could underlie PFS. Even without consideration to the entire history of this issue in terms of patient experience, neither a genetically defective 5ar2 nor maximal pharmacologic inhibition of 5ar2 resemble PFS. Subjects with globally defective genetic 5ar2 such served as the basis of expectation for pharmacological inhibition of 5ar2 with Finasteride during the development of the drug. Per Stoner in 1990:

…A systematic biochemical investigation was undertaken which led to the conclusion that these affected male children are genetically deficient in 5a- reductase and are therefore unable to metabolize T to DHT. The clinical features which define the genetic syndrome of 5a-reductase deficiency have provided a model for predicting the biologic effects of chronic inhibition of this enzyme in the adult male .

Neurological symptoms are not present and libido plainly observed as “normal” in this adult cohort without functional 5ar2.

Accordingly, there was no correlation of symptomatic severity to 5ar2 methylation in the CSF of half the small PFS cohort in Melcangi’s recent pilot study. There is not a remotely plausible mechanism for the crash after cessation of an exceptionally potent enzyme inhibitor, which in many cases has happened after a temporary partial or full remission of on-drug effects. In short, a total shutdown of 5ar2 does not mimic PFS.

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#3

Any theory that 5ar is the issue doesn’t seem to hold weight because many of us have tests showing normal 5ar activity also taking 5ar reduced steroids i.e. masteron or proviron does not work as it should.

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#4

I don’t believe the the expression of 5ar2 is based on one gene but thousands that are produced in local tissue that are independent from this gene. If someone has a defective 5ar2 and DHT was no longer being produced in tissues then their bodies would simply break apart which isn’t the case. Also those who have taken Finasteride while on it have experienced cognitive issues, erectile dysfunction so I don’t think it’s plausible to suggest that while inhibiting 5ar2 that people don’t experience symptoms that simulate PFS. The crash I think is methylation of site specific tissues that inhibit DHT from activating usually in the brain and CNS were there is high concentrations.

#5

I’m talking about site specific activation of DHT which is 10x more potent that serum you can’t check for this.

#6

So what? Applying dht on some parts like penis for a long time will heal it?

#7

We have one anecdotal report from Sibello who was using transdermal DHT applied locally to tissue who seen a 60% improvement in libido and it also took away his knee pain when applied directly. Note: I think he did this protocol for 6 months but he also crashed when taking away the DHT gel from penile tissue for 2 days which probably acted similarly to Finasteride.

#8

A lot of PFSers were doing andractim on the testicles about 6-10 years ago. Dr Andrew Rhyne in Ireland was recommending it. I don’t believe anyone recovered from it.

#9

I don’t believe Sibello applied it to the testicles. Also I wouldn’t expect a recovery per say as it would need to be applied daily for maintenance. This wasn’t the point of my post so I don’t want to get side tracked on therapies that may be potentially dangerous.

#10

No i dont want to do this. I’m just asking what can be done about site specific levels in order to improve our condition. There were no studies that masured tissue levels dht?

Oh and what about guys who are using dutasteride with no adverse effects? Their 5ar is basically switched off and they still have normal functions.

#12

Even if there was maximal inhibition of DHT the receptors would still upregulate in response to low concentrations which is precisely what happens when taking Finasteride or Dutasteride this is not the same as having methylation of thousands of SRD5A2 genes in certain tissues were DHT is no longer being activated. I believe there is thousands of the same genes located all over the body that are self expressed not depended on one gene.

#13

i crashed from dutasteride too

majority of population can use these substances without a problem

its those of us that are (likely) genetically predisposed to it that have this problem

#14

I should state everyone that whatever I say is theory based and my own opinion not facts until the science becomes concrete. Just keeping in check with the guidelines :stuck_out_tongue:

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#15

A guy on reddit told me his buddy put dht cream on his dick and had a speedy recovery (although it accelerated his baldness). This is obviously super anecdotal though.