This is an extremely important paper that may hold the key to solving PFS. I am reposting it from the original post: https://www.pnas.org/content/pnas/88/18/8044.full.pdf
I would be curious to hear what people think about it and the additional points I make below.
Quotes from the paper:
<<These findings indicate that dihydrotestosterone itself controls prostate growth and Sa-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5a-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.
These findings imply that dihydrotestosterone controls its own rate of synthesis in a positive manner.
A striking finding is that dihydrotestosterone, the product of 5a-reductase enzyme, positively regulates the expression of the 5a-reductase gene.>>
The article suggests that 5a-reductase activity is promoted by DHT. Therefore, low levels of DHT will downregulate 5a-reductate (paradoxically).
Some additional facts about PFS that check out with the article’s findings.
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Many people get PFS when there is a sudden DROP in DHT concentrations. That’s how I got it - from one 5mg pill of Finasteride upon resumption after a period of cessation.
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I have extremely low DHT, high Free T and high Progesterone. This may indicate malfunctioning 5a-reducatase.
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From Melcangi’s latest study: “In fact, PFS patients showed higher serum and CSF testosterone levels than healthy controls, while other neuroactive steroids, also including DHT, were suppressed”
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Not all PFS patients exhibit this hormone pattern and this may be due to variation of other important variables - such as body fat percent, insulin sensitivity, etc. For example, differences in body fat percent may affect amount of E2 produced as a response of higher T levels, which will change the presenting balance of hormones.
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We need to be open to the idea that there may be more than one way PFS may be induced as well to the idea that not all post-finasteride symptomatic patients have true PFS.
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From Melcangi’s latest study: “For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients.” Note: this is the gene encoding for 5a-reducase II enzyme.
Putting all this together, one would wonder whether DHT supplementation may be able to restore 5a-reductase activity. I know people have tried this and the effect has only been temporary (or there has been no effect, or they have gotten worse).
This lack of long-term effect may be due to negative feedback mechanisms where the body suppresses the HPTA in response to the rising DHT levels, which downregulates endogenous 5a-reducase synthesis - or has other oppositional effects.
There is evidence that such adaptation happens in response to DHT supplementation - in this paper originally posted by @Mew:
“Serum concentrations of LH, FSH, E2, T, and SHBG decreased significantly during DHT treatment.”
https://www.ncbi.nlm.nih.gov/pubmed/11932266 .
To oppose such an adaptation and to force the change to happen at the gene expression (and AR sensitivity) level, HPTA hormones (T, LH, etc?) may have to be supplemented as well, and E2 controlled. This will not be easy as there are many feed-back loops in the body, including through estrogen, SHBG, etc.
One way to attempt to achieve temporary high DHT concentrations before other hormones downregulate is through a series of cycles with high-dose DHT supplementation. This has been proposed before (although I don’t understand all of the logic explained here).
Anonymous user's theory: DHT treatment to increase 5AR2 expression .
To test this hypothesis, I intend to try cycles of a DHT cream for two days combined with a high dose Tribulus for 4 days (for lack of a more sophisticated HPTA maintaining TRT protocol). This is unlikely to work quickly but may have a positive effect over time.
I have already tested my blood before and after Tribulus cycles and I know that my T, E2, LH, FSH, and Progesterone all rise due to Tribulus.
The question is how to avoid a crash when supplementation is discontinued. It seems that a cycle approach may be counterproductive in that regard.
Update: On a second thought, this kind of cycles may lead to a crash, as at the end of each cycle one might end up with lower T and possibly lower DHT. It may be important to carefully control T and E2 and discontinue supplementation very gradually instead. Thoughts?
Ideally such experiments would be done in an animal model, where all variables can be controlled and measured precisely. I have long appealed on this forum for the need for such empirically-driven animal studies that we can easily fund, but to no avail. (Notice bitterness).
I admit that I have read very little about androgen biology and no doubt things are a lot more complicated and multi-layered than this. However, the solution does not have to be complicated, at least not from an applied point of view (as long as it is executed properly), just as the PFS-inducing cause was simple enough.
I would appreciate any comments - both on the theoretical aspects and on the proposed protocol.
