Nice post. Another possibility I haven’t seen here is that the metabolic pathway is broken.
You pointed out a cascade from T to DHT and other downstream compounds. If this metabolic cascade is broken, then it wouldn’t help to introduce T or any of the downstream chemicals, because the body is no longer capable of completing the metabolic process from start to finish.
How about this study @Sibelio
They treated rats with fin for 20 days (rather than one as you propose):
Diviccaro S, Giatti S, Borgo F, et al. Treatment of male rats with finasteride, an inhibitor of 5alpha-reductase enzyme, induces long-lasting effects on depressive-like behavior, hippocampal neurogenesis, neuroinflammation and gut microbiota composition. Psychoneuroendocrinology. 2019;99:206-215. doi:10.1016/j.psyneuen.2018.09.021
https://www.sciencedirect.com/science/article/abs/pii/S0306453018305067?via%3Dihub
By the way, this is a second study (in addition to another cited above) which finds adverse effects on the hippocampus.
@dj91 It can’t hurt to share these hypotheses – but to test them, a carefully planned study is needed.
I have already written a lot about what I believe to be the etiology of PFS and I have also put together a lot of hitherto unrelated evidence in corroboration of this theory. I have also tried to address all challenges to the theory I have seen and I am looking forward to new ones.
Following the formulation of this theory (and not before that), I have begun testing it on myself using transdermal DHT in various ways, with great success. I am now going to briefly describe my latest finding, which is more significant than any of the previous ones.
I reached a new level of improvement with the DHT cream. I can now hold an erection for prolonged periods of time and get aroused when I need to without Viagra. (The feeling of) Libido has improved as well. I definitely feel more “horny” and more interested in sex.
The new thing that I did is I started applying the DHT cream, in addition to the penis and lower abdomen, also to the following two areas:
A wider area on the perineum all the way to the anus and around. Before I was putting a small amount of cream in the middle of the perineum. Now I am am applying a bigger amount along the entire area from the base of the penis all the way to the anus as well as on and around the anus.
Inside the rectum: around the sphincter, on top of the the prostate region and beyond. I think what’s being affected are the prostate and the Pudendal nerve which is most accessible through the rectum. Note: I still don’t know why this works - because of the prostate of because of the pudendal nerve. I am still experimenting to see what location of application produces the biggest effect - whether on top of the prostate or along a wider area inside the rectum.
I decided to try this method after I looked where the Pudendal nerve is situated and noticed that it lines the outside of the rectum very closely.
The difference in effectiveness between this new method of application and the old method is substantial.
After I apply DHT in this method, I am up to about 66% of sexual function and I believe I can be functional for all practical purposes. My PFS baseline is 2%. This is making a huge difference in my mood as well, as you can imagine.
There is a lot of evidence that erections and sexual arousal and pleasure depend on NO being released in the Pudendal nerve and in the other key sexual tissues such as penis and prostate, which happens under the influence of DHT in healthy men.
This is a very significant finding and I believe it is a direct confirmation of the theory about lack of DHT in key tissues responsible for sexual function.
It would be interesting if other people are able to get similar results. If anyone decides to try this, please read all my disclaimers above and elsewhere about the possible risks of using DHT on androgen dependent tissues.
So far one person has already reported to have replicated my results at least partially, with my previous application method.
@orthogs @anon5006275 @anon22245532 @Famajor @Dubya_B @slavoushka @tisho1012 @airforlife
I have considered the possibility that rectal application is effective due to higher systemic absorption of DHT. No doubt bioavailability of DHT from the rectal administration will be very high indeed. However, the evidence I have collected supports the alternative explanation that the effect is due to higher local tissue concentration.
Here are some of the reasons for this conclusion:
First, most of the DHT I put on regular skin gets absorbed already, although perhaps a bit more slowly. I have used different topical formulations and none of them leave any residue on the skin after some time.
Second, I am very sensitive to the overall systemic dose of DHT due to tangible effects on heart rate, breathing, joint pain and mental function. I make sure that total systemic dose remains the same through the feedback I get from these systems. If I am reaching higher serum DHT concentrations with the new method of application, I would notice the systemic effects.
Third, I can actually feel the effect of DHT on the tissues as a sensation of slight and pleasant warmth - as if you actually have an organ there and not the complete absence of sensation that is typical for PFS. This is evidence that local concentration matters and it makes these tissues feel more normal.
Forth, I actually put very little of the total dose in the rectum. Maybe 1/6th of the total dose.
Fifth, I get a good chunk of the effect even if I don’t use any DHT in the rectum or on the anus but only on the perineum. Still I get less of an effect if I skip the perineum but only put it on the penis. And I get no effect if I put it on non-genital skin.
I just stumbled across this study which @Demon posted here:
Dihydrotestosterone stimulates 5 alpha-reductase activity in pubic skin fibroblasts
DHT (10(-7) M) increased 5 alpha-reductase activity 2- to 4-fold over the control levels.
I can’t make total sense of it but I think it’s related to what @Sibelio is sayng: that the location of applying DHT cream makes a difference. Does the perineum count as pubic skin?
I think the point is that 5ar is positively unregulated by DHT, which of course is a counter-intuitive finding. I have posted papers about this before.
The results I am getting may not depend on this mechanism but purely on higher local DHT concentration. After all the effect is not self-sustaining and goes away when I stop applying the cream.
However, I may be observing some early potential evidence to the contrary, although I don’t want to speculate about that yet. Perhaps there can be long term improvements in 5ar expression if a higher DHT milieu can be achieved.
Here’s a rare disease called 5-alpha-reductase deficiency:
NIH GARD: 5-alpha reductase deficiency
It can lead to a genetic male developing:
external genitalia that appear female. In other cases, affected individuals may have ambiguous genitalia. Others may have genitalia that appear predominantly male, often with an unusually small penis (micropenis) and the urethra opening on the underside of the penis (hypospadias). This condition is caused by mutations in the SRD5A2 gene and is inherited in an autosomal recessive pattern.
Clearly 5-AR is a key enzyme to ensure proper development of male genitalia. Probably also maintenance of the genitalia’s functions once the male is mature, which explains our predicament: we still have a penis, but without 5-AR the penis can’t function normally (maybe this is obvious and many of you know this already).
Does DHT cream work because it’s providing DHT directly, without having to depend on the T -> DHT metabolism, which is broken because of the 5-AR deficiency?
Here’s a post on using DHT cream, on a penis enlargement forum (a practice I do not endorse and am skeptical of) back in 2011:
https://phalloplasty.proboards.com/post/2756/thread
Here is a relevant bit:
It is currently being used to treat micropenis cases with some success it appears. It also is used to treat low libido and Gynecomastia (man boobs). It is also currently being studied as a treatment for enlarged prostate. One of the side effects reported in the first prostate study (done in Britain) was improved erection quality.
Wow, exciting development Sibelio. Let us know if this sticks.
Pharmacokinetics of testosterone cream applied to scrotal skin
We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route.
I have read multiple papers about the use of topical DHT creams (but not systemic administration of DHT) for penis enlargement in people with genetic 5ar deficiency who have a micro penis. It does work, although to a limited degree.
To the extent that it does not work well enough, the authors have concluded that it is very hard to get the DHT into the tissues. Their area of application was more narrow than what I use, however.
I try to apply the DHT on the lower abdomen as well as on the penis as there are a lot of blood vessels in that region going down into the penis. Ditto about perineum and all the other areas I talked about.
Note that topical DHT is used in these studies as systemic administration cannot achieve the same high level of tissue concentration.
This is the key argument I have been making about the difference between systemic use of Proviroin, which does not appear to work, and topical use on genital tissues. It is contingent on the fact that these key tissues require DHT concentration 10 times as high as in serum.
@Sibelio
I have used AndroGel TRT for the past four years. My “Google research” convinced me early on that applying the gel to my balls and perineum would result in higher absorption than application to the shoulders.
I’m pleased that this study backs that up. Thanks. Jim
I believe so. The alternative argument would be that we already have enough (normal levels of) DHT in these tissues but this administration is just supercharging the tissues with even more DHT, which shifts the sexual function curve up all other things being equal. I do not believe this is the case. I may explain why later.
In fact, the dominant theory has argued that adding more DHT would downregulate the system further and a worse outcome will be achieved. Similarly, it has been argued that DHT might boost the system initially but then a lower baseline would be reached following the subsequent downregulation.
I have not observed such effects with my method. The positive effect of DHT has been consistent and has not weakened over time.
It has to be noted that oral DHT administration MAY have worsening effect on PFS symptoms according the following theoretical mechanism.
If we assume that 5ar2 has been selectively silenced and DHT in key tissues responsible for sexual function is low to zero but in other tissues is normal to high (due to higher serum concentration of Testosterone intended to compensate lack of 5ar2), then systemic administration of DHT will suppress Testosterone production. The net effect on libido from higher serum DHT but lower serum T may be negative. We already know that lowering DHT increases Testosterone and the opposite has been shown as well.
A theory of the pathophysiology of PFS: finasteride, or discontinuing finasteride, permanently disrupts functioning of the SRD5A2 gene. This gene might be responsible for producing the 5-AR enzyme, which in turn metabolizes T to DHT.
Reasoning:
Melcangi et al paper noting methylation of SRD5A2 in CSF of PFS patients
https://ec.bioscientifica.com/view/journals/ec/8/8/EC-19-0199.xml
Link between the rare disease 5-AR Deficiency and SRD5A2 mutations as noted here:
https://rarediseases.info.nih.gov/diseases/5680/5-alpha-reductase-deficiency
This condition is caused by mutations in the SRD5A2 gene and is inherited in an autosomal recessive pattern.
There is a lot more that goes into reasoning than this. I have described it in detail above. True, I need to write a proper summary.
@anon22245532
“…Have you posted here about your results with AndroGel?..”
Just searched my records.
My first check, pre-Androgel, showed total testosterone at 38 on a scale of 72 to 623. This was the only time the free testosterone was checked, and it was .91 with a scale of 3.67 to 13.9. Both low obviously.
Since then, on AndroGel, my total test has been checked twice yearly:
667, 231, 544,
681-immediately before Proscar
283-Four months post-Proscar
75-without AndroGel last month
Do these numbers help in any way? Jim
This is something which I suppose may well be the case too.
Sibelio, you must be very careful to avoid ‘step changes’ in androgen levels by say, stopping to apply the cream all of a sudden. You’d want to avoid creating a similar condition to what Finasteride would do to DHT levels. It may cause upregulation of receptors and other unknown mechanisms.
But you’re pretty switched on, so I know you’re aware of the risks, as you’ve stated previously.
Yes, it is a risk. I currently apply the cream only once a day, at night, and I go into very noticeable withdrawal with unpleasant side effects before I apply the next dose. So concentration is fluctuating a lot which is not good.
It is very hard to be constantly dependent on something and manage it well, especially if takes so much time and effort to do properly.
The other thing I have noticed is some prostate pain and difficulty urinating. I don’t know if prostate can get enlarged in 4 days. At any rate, this is a very risky procedure.