Research on the regulation of 5a-reductase

Another interesting excerpt from the most recent paper above:

“The pattern of expression of 5α-R type 2 presented in this study appears to be correlated with T levels, indicating that this isozyme may be positively modulated by androgen, as described previously during late fetal/early post-natal life (1). Our results demonstrate for the first time that 5α-R type 2 expression in the brain is regulated by DHT, a product of the encoded enzyme, via a form of feed-forward regulation. This regulatory mechanism is common among developmentally important genes.”

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Can you give citations from the literature showing substances X, Y and Z - whatever substances you had in mind that are accepted to cause PFS - have no effect on 5ar? Very soon I will be doing the opposite - showing the effect on 5ar of other substances.

Also, I am curious, how do you imagine substances wreck the AR if they have no effect on androgens?

There is a lot here. First, there is no paper showing the etiology of PFS so obviously conjectures have to be made using papers about other things. I don’t think I have ever made any logical “jumps” using a paper, not any more than any unproven theory has to do. If there is a concrete jump you had in mind, I would like to hear.

In the Melcangi paper you give as an example I make no “jumps” for the simple reason that I have argued there are two types of PFS long before his paper came out. That there may be two types of PFS there exists a lot of evidence, in addition to the that presented in the Melcangi paper.

First, there are two distinct ways of getting PFS - one when DHT goes down and one, supposedly, when DHT goes up. Second, some people recover fast and completely, others not at all. Third, some people have low testosterone, others have normal testosterone. The list can continue. I have talked about this elsewhere.

It is very common in medicine for a similar set of symptoms to have different etiologies. This is not the exception but the norm. For example, a cough can be caused by pneumonia or lung caner or emphysema. Similarly, sexual dysfunction can be caused by low tissue levels of DHT or low serum levels of Testosterone (or by high Prolactin, etc). The idea that there is more than one type of PFS is not outlandish at the least.

In our previous discussion, where you repeatedly refused to answer my very simple and direct question how a single pill of finasteride causes PFS according to your chosen theory, I gave two possible explanations for Melcangi’s findings:

  1. There are two types of PFS - discussed above;

  2. 5AR2 is not methylated everywhere in the body to the same extent (but what matters the most for determining PFS status is 5AR2 in the sex organs and pudendal nerve). 5AR2 may not be methylated in some tissues (like in spine, which is what was tested in the paper) in some people because these tissues may have a relatively higher proportion of the other isoenzymes, which protected DHT from dropping too much in these tissues when 5AR2 was inhibited. This is almost necessarily true, not just likely true.

  3. I can add this to the list - and I have no problem at all listing it as a possibility because I am a lot less fanatical about my theory than you are about yours - 5ar2 is not a factor in PFS. I think however this is the least likely explanation.


Ocam’s Razor: I can’t think of a more simple and parsimonious theory of PFS - that I believe can explain all symptoms of the syndrome - than the inactivation of a single gene. Can the same be said about the theory you support? Note that I do think at least a thousand genes are affected in PFS, as I have written before, but that may be easily explained by the fact that these genes are androgen-dependent and thus affected by DHT.

There are lots of potential ways to answer this. Biology is a lot more complex than you seem to appreciate. First, exercise does a million things and each of them can be the cause of this. Second, if we assume that exercise raises DHT, although not ALL types of exercise raise DHT everywhere and to the same extent - it is quite possible that androgen deprived tissues react with pain (again, for a million possible reasons) when androgens are increased at first. I personally experienced this after I stopped Finasteride (but I think before I got PFS later on upon resumption of Finasteride): I had pain in the penis, testicles and perineum for a very long time.

I know someone else as well who got prostate pain when he exercised. He eventually recovered from PFS in all likelihood due to daily exercise.

Worsening of sexual symptoms: this needs to be carefully defined and explained but I think it is fairly well accepted that immediately after exercise for at least 24 hours but probably 48 or longer with higher intensity exercise libido and sexual function are greatly reduced.

Insomnia: Again, insomnia can be caused by any of the million things exercise does but also - is there a more general and less specific symptom than insomnia in medicine? I don’t think anything can be argued based on insomnia alone, let alone reject a mountain of evidence for a theory.

Finally, it is important to stress that a set of evidence in a given experiment is usually consistent with multiple theories. Ultimately, all possible theories from all available experiments need to be examined together to determine the most likely answer. That’s what I am doing, to the best of my ability.


The burden of proof isn’t on me to show that substances that cause PFS have no effect on 5AR. Substances such as Lupron, SSRIs, etc. have no effect on 5AR yet seem to be causing the same symptoms. These substances are demonstrably anti-androgenic (to varying degrees), yet they exert this effect in different ways. (Lupron:, SSRIs:

They can (androgen receptor antagonists have no appreciable effect on serum androgen levels) but I didn’t imply that that was the case here. I’m just saying 5AR isn’t the only enzyme/path that affects androgens. 3A-HSD induction (which is what many SSRIs do) results in a reduction of cellular androgens, etc.

Before I respond to the rest of your post, I must ask, do you believe that Finasteride, Isotretinoin and SSRIs cause the same disorder/syndrome? Or do you believe this is something that’s unique to Finasteride?

This isn’t worth much from a scientific perspective but I will share my experience. I first took SSRIs when I was 14 or 15 for about two weeks, and it had an impact on my libido, genital sensation, and caused some minor changes to my emotions (slight anhedonia, not as much motivation). The mental issues largely resolved when I started working out, but the sexual ones did not. It did not bother me because I did not even realize I had an issue. Then the first time I took Finasteride and came off of it, I finally understood why people were so crazy about sex. The first time post this incident, I came from sex for the first time ever and it felt unlike anything I had ever experienced before. My sensation was strong, and I was completely shocked when I orgasmed because it had never happened in the previous 2 years. Whenever I had sex, I could go on forever but I had to manually finish myself off. I was never completely lost in it, I enjoyed it but I didn’t think it was all people made it out to be. This was a profound experience for me, but I couldn’t think of any real explanation for it. My concentration and drive were also much better (I never noticed the deficit because I had a good baseline to begin with). This lasted until I took Finasteride again and crashed, got better over two weeks and crashed again.

Now the reason I’ve detailed this entire experience is because I think it’s possible that people have taken antiandrogenic substances over the course of their lives (supplements, diets, lifestyle changes, etc.) and it primes them for this, just as if taking a short course of an antiandrogenic substance. There are people here from things like soy protein isolate, which I for one never would’ve thought twice about consuming in the past. Gene expression is dynamic.

Not impossible, which I have no problem with considering either. I just think it’s more likely that most of us are suffering from the same disease to different degrees. If you look at axo and awor’s literature review that they posted, you’ll see that they’ve written about this at length. SBMA is genetic disease whose phenotype is replicated by genetically engineering mice to have overexpressed AR. In disease models like SBMA, the degree of AR overexpression effects the degree of toxicity exhibited in response to a ligand. It can be overexpressed such that androgenic functioning is enhanced, it can be further overexpressed such that androgenic functioning is partially compromised (where people take T/DHT and feel nothing/not much), and finally, it can be overexpressed to a state where in response to a ligand, instead of having an androgenic effect, it has an antiandrogenic one (taking T/DHT and feeling worse). In SBMA, various factors such as age, genetics, etc. also play a role in determining the degree of toxicity.

Now my take is that majority of the people over here have this as it accounts for the symptomatic heterogeneity well.

My experience at the time was that although I wasn’t back to normal mentally, I would engage in some form of sexual activity once a day and had spontaneous and morning erections most days. The days post exercise I could barely get an erection, much less feel like engaging in sexual activity. I’m not sure if you’re talking about in the context of PFS, but pre PFS, I never experienced anything even remotely close to this, no matter how hard I worked out.

Anyway I appreciate the response and I hope you take the time to really give some thought to what I’ve said, and I’ll do the same for what you have.


Have you considered taking your thoughts on this and reaching out directly to the researchers included in the papers you’ve listed? I’d assume they have an expertise in these areas that far exceeds many of us here.

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My transforming growth factor-beta 1 (TGF-beta 1) was high in my last blood test.

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