Can someone explain if/how neurosteroids are affected and what it means?

General Discussion
#61

Thanks a lot. I heard from people who got PFS from a single pill, but I thought it is due to the irreversible binding to the enzyme, so that the enzyme receptor complex is slowly cleared from the blood, which itself could lead to rising DHT levels that silence the 5ar-gene in a feedback loop.
I also thought the the upregulation is just a sign, that DHT or following cascades are too low or not working anymore.
PFS within 20 minutes turns down most of the theories that made sense to me.

Because I heard people get PFS when they reduce finasteride and because of the dominant theory I decided to tapper of finasteride super slow: the first 800 mikrograms over 5 months and since 9 months I tapper down 0.5 micrograms a day.
Reaching 230 micrograms I crashed (while tappering off mirtazapine - probably I had the crash already 1 year before but could cover most symptoms with mirtazapine).
Another thing that I notice were morning errections came back in waves under 180 micrograms, but they were oftentimes so long and painful that I woke up from it (contrary to what one may think they were not coming with any pleasure or sexual desire, they were completely disconnected from my brain). These hyper errections took place until under 100 micrograms although I went down less then 0.5 sometimes just 0.3 micrograms a day! I am still tapering off (73 micrograms now in 2 daily doses). The insomnia and mental symptoms are hardly bearable. Sex life is rare and not connected to much pleasure.

I would also support that there are various types of PFS (I think it depends on which organs are most affected by the 5ar-silencing). Does your type of PFS include mental problems like insomnia? And what where the first symptoms you experienced after 20 minutes? Were they different from what you experienced after 4-6 weeks (full clearance of the finasteride-enzyme-complex)?

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#62

This is what my experience felt like as my mileage decreased and my weight increased while energy slowly decreased like clock work…As if something was slowly leaving your body month after month until you are just now left as an invalid slob…

#63

Does finasteride affect the brain of everyone who takes it or only those who develop pfs?

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#64

Why does pfs then only happen to some people? Is it only some of us that that finasteride that it effects our brains?

#65

It 100% affects everybody…I was always someone who dreams a lot, and very lively dreams, and it might seem stupid, but i had solved lots of my problems dreaming of solutions for them (Even maths problems, and im really not lying)…
I took that poison 3 years, during which i stopped dreaming all at once…I always thought, it must be im getting older, or too much stress at work, but boy i was wrong…3 years, and my libido and errections were intense like when puberty hit, and BAMMMMM everything is dead, 0 Libido, 0 errections…But at least im dreaming again now, so i know 100%, that it was that poison, that fucked up my brain

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#66

Are you still tapering off that and how long have you been on it? This by itself can lead to psychological and neurological side effects for years after you stop completely, depending on how long you were on it.

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#67

No, I was on mirtazapine for 1 year in varying doses and try to cut it several times.
The crush was actually following the last doses of mirtazapine. I was reducing finasteride the same time, so it is difficult to say what is causal. The symptoms fit to PFS as it is not just neurological. Mirtazapine is also changing some Neurosteroide and cortisol pathway, therefore my best guess is finasteride first caused insomnia and tension, taking and tapering mirtazapine worsened the symptoms to full blown PFS

#68

The erections got first stronger when you stopped it?

#69

In addition to the simple test described above, another simple way to test the theory I advocate for is to have a double blind randomized clinical trial with rats. To my knowledge, no such study has been done before.

Rats in the treatment and placebo groups are given a single dose of finasteride or placebo. Sexual function and 5ar2 expression are measured before and after the experiment. Rats with permanently reduced sexual function are identified.

Prof. Melcangi of all people should be willing to do such a study. What study is he proposing to do instead? We have no idea as the PFS Foundation has announced no details, even though it is asking for contributions for the study.

@PR123

#70

I don’t think rats needs placebo :grinning_face_with_smiling_eyes:

#71

As someone without much knowledge of the hard science behind all of this, your theory makes sense to me. Sibelio, What do you think of the Possibility of some people having BOTH types of PFS?

If your hyphotesis is true, it might be what happened to me. I had “immediate” side effects that appeared quite quickly(it’s been a while, but i would say within 1 month of treatment), such as non existing morning and spontaneous erections, lack(or much weaker) Visual Lust, and lower libido etc. These are some of the side effects that still haunt me to this day(more than 2 years after stopping Fin).

However, i also had 2 of the infamous “Crashes” in which i became virtually asexual and had a dead penis. The first one made me have a break of ~6 months from Fin, and the second one made me stop using it altogether. These are the terrible “sides” i’ve had some success in recovering from, merely through time, specially in the first 3 months after stopping the medication, but with some degree of recovery up to 1 year after it. I’ve also had some mental health issues that happened somewhere in between starting and the crash, but these seem ot have resolved mostly.

I believe my current status is quite similar to how i was post-fin but pre-crash(a bit better maybe).

That’s interesting, because both my crashes happened while i was still taking Finasteride, they were the reason why i stopped. But i still think rising DHT(Or other androgen) might’ve still been the cause, Why?
You see, in retrospect i realized that both my crashes happened in very specific and unique moments of my life. When i started a relationship with a girl(I only had relationships with 2 girls during my Fin use). Why is this relevant?

https://www.sciencedirect.com/science/article/abs/pii/S1090513803000539

This may seem far-fetched(bear with me, i’m no expert). But could it be that these events triggered a rise in Androgens that messed with my hormonal homeostasis?

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#72

@Sibelio As the thread gets longer: do you think you could summarize your neurosteroid explanation (or whatever you want to call it) in one paragraph?

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#73

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.

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#74

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.

#75

@dj91 It can’t hurt to share these hypotheses – but to test them, a carefully planned study is needed.

#76

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:

  1. 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.

  2. 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

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Ejaculation without sensation treatments
#77

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.

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#78

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?

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#79

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.

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#80

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?