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

I was wondering if anyone could briefly explain what neurosteroids are and if they are affected by finasteride? Im asking because ive seen different information, some say that fin depletes neurosteroids such as allo and that this could be really harmful for our brains and one one of the biggest causes of side effects. On the other hand ive also seen people say it does not effect them in most people, probably because fin acts on 5a reductase type 2 and this type is not present in the brain or important for neurosteroid production, rather it is type 1 and 3 which are important and they are not effected. So therefore fin would not deplete neurosteroids.

Can anyone clear the air on what the truth is or just offer some information regarding what we do and dont know. To me the neurosteroid theory makes a lot of sense but I am in no way any kind of expert and so I really dont know what im talking about.

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Read section 3, Potential adverse effects of 5α-R therapy on the CNS.

You won’t find this on Wikipedia. Guess why.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064044/

I actually did read something on Wikipedia that this drug reduced neurosteroid levels in patients with pfs so its actually where I first read about it.

Is dht and 5a reductase type 2 still important for brain function or its only type 1 and 3 like that one user said?

While i cant actually 100% explain how finasteride (Who is only supposed to block type 2 ar) leads to diminshed Neurosteroid production, we do actually have some clear data indicating, that PFS patients have a pretty clear low level of these neurosteroids (Is it just a consequence of other mechanism invlovng the androgen receptor, or is it the main problem leading to all other symptoms, noone can answer that question right now)…Im working on it though so stay tuned my man :D…

"The CNS has the capacity and the machinery to synthesize a host of neurosteroids [72]. Neurosteroids play a pivotal role in modulating neural activity through interaction with neurotransmitter receptors and neurotransmitter-gaited ion-channels [73]. These neurosteroids interact with a host of neurotransmitter receptors and modulate seizure susceptibility, anxiety, stress, and depression [74]. 5α-R reaction is the rate limiting step in the conversion of testosterone, progesterone, cortisol, corticosterone, and DOC into their respective 5α-dihydro-deratitves, which serve as precursors for 3α-hydroxysteroid dehydrogenase which transfroms such precursors into their respective neurosteroids (androstanediol, allopregnanolone [AP], tetrahydrocortisol, tetrahdyrocorticosterone, and tetrahydrodeoxycorticosterone) (Fig. 1) [1,2]. All three isoforms of 5α-R are expressed in the various regions of brain and are thought to be critical for brain development since fetal brain express high concentrations of 5α-R [1,2].

It has recently been shown that patients who had been treated with finasteride have reduced or undetectable levels of neuroactive steroids in their cerebro-spinal fluid and plasma, and exhibited higher levels of precursor steroids [75]. This observation strongly suggests that 5α-RIs have a deleterious effect on the biosynthesis and function of neurosteroids in the central nervous system. Finasteride treatment resulted in decreased levels of 5α-DHT and 3α, 5α-tetrahydroprogesterone (AP) and increased levels of testosterone supporting the hypothesis that deleterious effects of finasteride may be persistent or irreversible. This may explain some of the noted symptoms such as anxiety, depression and suicide in patients who have been treated with finasteride [76]."

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“In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses.”

There should be absolutely no doubt in you that every one of the 3 types of 5a-reductase is crucially important for everything in the body, including the brain. The notion that type 2 is less important, that it is not present in the brain, or that DHT (or any of the other 5a-products) is not important - either in the brain or elsewhere - is totally insane. Such a thing can only be claimed by Merck, as it has been.

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@Sibelio It always strikes me as odd on this forum, why we aren’t simply focused exactly on this study. This is really the only study that has any demonstrable evidence for the issues we face, yet we’re chasing all these random protocols all the time - pumping up our androgens, taking oddball supplements, coming up with crazy theories (theories that may in-fact make sense, but aren’t backed by evidence like this study). To me, it seems THIS is exactly describing what’s happening to us, and the longer I have this issue, the more I’m convinced it’s all deriving from the brain. That’s not to say it’s psychological, but the more I’ve grown intimate with this syndrome, the more I feel it is a fundamental breakdown in the chain-reaction of brain functioning with regarding to libido and reward centers. This has been caused by neurosteroid depletion/inability to create neurosteroids (malfunctioning 5AR) leading to outright brain impairment due to the use of FIN. When I do have those brief moments of recovery, EVERYTHING works again, the physical symptoms disappear along with the mental, but it all seems to be something that is baseline neuronal; and no boosting my androgens ever causes these recoveries to occur.

I would think we would all focus all our efforts on trying to address this, and this alone? It would seem understandable that protocols addressing the gut, as well as diets reducing inflammation, reducing our food intake and living to it’s bare essentials, would all have affects on brain signaling, and also understandable how these protocols would only cause temporary recoveries as well. Obviously this will sound futile or somewhat short-sighted, but I often wonder if we can explore these affects on the brain, or a malfunctioning 5-AR, and design some kind of protocol to address what’s occurred here.

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All the evidence I have seen so far - in the literature and in real life, my own data included - points in the direction of malfunctioning 5a-reductase. The benefit of this theory, as of any theory that is a candidate of being a true theory, is that it explains all the available evidence - including the low neurosteroids, and including the physical changes - shrunken dick, etc.

I have written more about this in this post and in the last post of the same thread. Tribulus stopped working. What else works?

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How do you explain that taking exogenous DHT (proviron) doesn’t even provide minor improvement, or even makes symptoms worse, in the vast majority of cases? That’s the reason why no one believes in this theory.

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Serum DHT levels are a poor predictor of tissue-specific DHT levels. So proviron may boost serum DHT levels, but this may well not translate to tissue-specific levels. This has been shown.

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I agree with the fact that they are poor predictors however for me the theory cannot be true because if the cause were androgen deprivation then you would notice at least slight improvement. How is it possible that not even a few molecules of proviron can enter the affected area and bind to the AR? If the cause of persisting side effects were androgen deprivation then even a minute amount of androgens would give significant relief. I have taken doses of 500 mg proviron for extended periods of time and noticed no improvement, in fact I even experienced worsening, my conclusion is that this theory is impossible.

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Hey @arkaeik, I hear you - this was the reason I was always confused as to why every time I tried DHT, it wouldn’t work. “Surely SOME increased level of DHT would have an effect, I mean this is why I took the hair pill in the first place - to reduce DHT!” I was convinced it was at the receptor level. I tried local DHT and Oxandrolone - and both really didn’t do anything for my symptoms. Local DHT had a moment of recovery, but then didn’t work at all.

Aside from the point that these drugs generally raise serum DHT levels, and our issues (I would think) are mostly related to brain and penile tissue specific areas (BBB issues may arise and so forth); we are also forgetting the other piece of the puzzle. The study above is meant to largely address what FIN does to our neurosteroid levels and its fundamental impact on our brain functioning and reward systems. DHT is but only one piece of the whole 5-AR ‘cascade’ so-to-speak, and only a piece of what a malfunctioning 5-AR would affect. Even if we had high levels of DHT (which, thankfully I do), if our neurosteroid levels are non-existent or impaired, then no amount of DHT will have an effect on our reward systems. We still won’t be able to get the full erections we’re used to, we won’t have the pleasure centers correctly firing for full libido & stimulation, and our mind-body reward system will be generally incapable of functioning like normally functioning male. I would imagine a malfunctioning 5-AR system would lead to a whole host of issues. Simply introducing increased serum-level DHT would seem to me like putting fuel into a car with no tires.

My goal with the above is to have a collaborative discussion though, I could be very wrong. This is a hypothesis I’m coming to based on years of back-and-forth on this forum, researching, and the testing of multiple protocols. @Sibelio please contribute anywhere where I may be incorrect.

First, as @orthogs mentioned above, raising systemic DHT will almost certainly not lead to preferential saturaton of important tissues. Research has shown that tissue concentration of DHT in prostate is ten times higher than in serum. That’s because DHT is produced locally in the tissues and the direction of transfer is from tissues to serum.

Second, if 5ar2 is damaged in certain tissues, that leaves 2 other enzymes to produce DHT in other tissues, which may be enough for serum concentrations to appear normal. Further, there is not a good correlation between serum concentration and tissues concentration of DHT, as per the same paper, which is cited in the following post of mine.Tribulus stopped working. What else works? Just because someone has normal serum DHT does not mean they do not have DHT insufficiency in certain tissues.

Third, people with PFS have been found to have higher level of precursor hormones (progesterone, free tesosterone). This is my hormonal profile as well. Higher level of precursor hormones is an attempt of the body to increase the synthesis of 5ar hormones, despite the malfunctioning 5ar enzyme.

Now, when serum DHT is raised through supplementation, this will fool the body that 5a-reductase is functioning properly through negative feedback loops, which in turn will decrease precursor hormones. It is not clear what the total effect on tissues DHT will be but it is clear that tissue concentrations of 5a-DHP and allopregnanolone will fall, as progesterone is reduced. This may lead to worsening symptoms.

I have personally observed this feedback effect. I have very high progesterone, well above range. When I started using DHT, my progesterone fell by 33%. This is described in the following post from the same thread as above: Tribulus stopped working. What else works?

Fourth, local application of DHT to the genital area works well for me. (WARNING: I do not recommend this as it may be carcenogenic.) It really matters where you apply it, how much you apply, and what the formulation is. In one of the posts above I describe the pattern of application that produces the biggest effect. No doubt such topical application cannot reverse all symptoms of PFS as DHT is lacking not just from the genital area but also from key nerves in the body and in the brain.

Fifth, I am not sure how many of you have joint pain, but I used to have extreme and highly debilitating joint pain. Administering DHT systemically all but eliminates the joint pain, depending on the dosage I use. This is extremely strong evidence that DHT deficiency is causative for joint pain. I hypothesize that soft tissues holding the joint together are DHT dependent and they weaken from lack of DHT, which results in weakened joints. I have additional evidence to support this conjecture (obtained before I even began DHT treatment), as the nature of my joint pain indicates it originates from the soft tissues (spreads along the muscles), and no joint abnormality was found on a MRI.

Sixth, Melcangi’s latest study clearly demonstrated that patients with PFS suffered from methylated 5ar2 gene. This is in addition to previous research finding low levels of 5a-DHP and allopregnanolone in spine fluid, as well as upregulated AR. The latter can easily be explained by low androgen signal due to low tissue DHT.

People have tried to argue that Melcangi’s study proves 5ar2 malfunction is not causative for PFS because only 50% of the sample had that finding. This is an extremely important point that needs to be addressed thoroughly, because failing to understand this point has held our community back for decades and will continue to hold us back going forward, no matter how much research is done on the condition. I may try to address it in greater detail in another post, but here is a short version for now.

Everybody knows and understands that changing the body’s hormonal balance exogenously can lead to a prolonged disruption of hormonal balance upon discontinuing the exogenous intervention, which manifests as hypogonadism. This happens in body builders who take various steroids and then discontinue them, and it is known as HPTA axis shut-down. This also happens in prostate caner patients who take a combination of anti-androgens (including finasteride) and then discontinue them. The latter group takes multiple years to go back to baseline. I may insert the chart from that study later.

Then why can’t we fathom that taking finasteride and then quitting can also lead to prolonged hormonal disregulation that will result in hypogonadism? In fact this disregulation may be very stable as a new equilibrium is established, and may need targeted intervention to change, although is likely to normalize over time by itself. In fact we have evidence that a fraction of PFS sufferers normalize with time. These PFS suffers don’t need to have any changes in gene expression to suffer from hypogonadism.

This is what Melcangi’s study shows as well - a fraction of people with PFS symptomology do not have gene expression problems. In other words, it is very likely that there are two types of PFS. What I would call PFS Type 1 represents hypogonadism secondary to hormonal disregulation. This type is likely to recover over time, especially as their androgen receptors are normalized.

Patients with the second type of PFS, PFS type 2, most likely suffer from malfunctioning 5ar2. This group is unlikely to recover following the same mechanisms as the first group. Put bluntly, these are the people who do not get better over time. They are also likely to have additional symptoms secondary to 5ar insufficiency that the first group may not have. It is important to note that this group may also have hormonal disregulation early on similar to the first group, in addition to having malfunctioning 5ar2, which may partially or seemingly completely resolve over time (but not upon closer inspection of tissue levels of 5ar hormones).

The two types of PFS, type 1 and 2, because they are very different conditions, are likely begotten in different ways. The first type likely happens after finasteride is discontinued and may be related to the degree of AR overexpression. The second type most likely happens suddenly, as a switch being turned off - including from a single pill of finasteride. This mechanism does not require any degree of prior AR upregulation.

Attempts to use one causal mechanism to explain both types of PFS is a mistake. This is manifest when people discount the role of malfunctioning 5ar2 citing evidence from people who do not have this irregularity. Similarly, a theory postulating the existence of a single causative mechanism cannot explain contradictory and apparently mutually exclusive circumstances of getting PFS (i.e. from a single pill vs. after AR upregulation and subsequent AR overwhelm). I talk more about this here: Initial Ideas - Working from First Principles

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The theory doesn’t make sense for one very important reason. Normal people who take proviron or other androgenic steroids will experience increased androgenic function in all different tissues. In fact proviron is often used in people with delayed puberty, and it works very well. This is proof that exogenous DHT does in fact reach androgenic tissues, but in people with PFS it must not have an effect due to an unknown mechanism.

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Backing up @arkaeik here. Anecdotal experience but I know (non PFS) friends who’ve taken DHT derivatives in the gym and they had pretty clear androgenic responses from it.

@Sibelio Your initial post doesn’t make sense. Why would anyone take DHT derivatives if all they did was raise serum DHT levels in a blood test while not having any effect on the desired tissues?

Also, you’ve stated that local application of DHT to the genital area works for you. I don’t know if you’re aware but Blackfox stated that applying DHT cream to his genital area literally shrank his genitals.

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@arkaeik and @borax Thanks for your comments! This is very helpful. I will try to respond later.

If anyone else has any other evidence or theory contradicting what I am arguing, please post.

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I have taken Keto-DHT-17 I think it was the name from Propeciahelp and notice effects on brain. Also took Oxandrolone and definetly noticed some pro DHT feelings also. Last time I took 5 pills and drink a lot and I was king of the dance floor and very good eye contact with girls, definetly something going on. I went after my last cycle with Oxandrolone to have some watery semen so I think t affected me somehow.

Last thin to comment is the week that I followed a brocolli + asparagus diet everyday, and last day I didnt took brocolli, I noticed a big surge in male sexual behavour pro DHT, And I thought it was because brocoli is know to block DHT to be in contact with prostate and then suddenly it allowed a lot (maybe more because asaragus Idk).

And how are you today in terms of libido and ED?

It is assumed that finasteride has passed through the blood-brain barrier and damaged our brains. GSK seems to be aware of this.

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