A not so crazy idea: reduce DHT binding to AR?

General Discussion
#1

Except for people who suffered from abnormally low T and DHT following fin, most of us respond pretty badly to anything that increases T and DHT. This is what typically happens: short term improvement, then crash.

Think about it, here are things that we are almost sure of:

  • when DHT was low our receptors (ar) were upregulated
  • when quitting fin those upregulated AR saw an unexpected surge of DHT, and a lot of us experienced abnormally high libido during these days…

What happened after? Were the receptors downregulated? We know something went wrong and it could be because the receptors did not downregulate on time, and somehow something happened that interrupted the normal functioning of the receptors…

This is taken from wiki:
“However, the use of certain receptor antagonists may also damage receptors faster than they upregulate (internalization of receptors due to antagonism)”

It is possible some damage occured to those receptors. This mean we had a lot of receptors but they were no longer doing their job correctly. They got messed up with the sudden change in the hormonal environment…

Correct me if i am wrong but upregulation means simply that there are more receptors. But it is possible that this shock has made each receptor less effective…they become desensitized to DHT…

Now whenever we take Something that increase DHT we feel better but rapidly the receptors maybe become even more desensitized to DHT which causes a crash…

People who take progesterone: you know that at some quantities that are high enough (and have no clue what this threshold is) the progesterone competes with with DHT at the AR. Yes so your cells start to get less DHT. You feel shit. But your receptors maybe start to become more sensitized to DHT and that what could have caused the persistent improvement in some…

In other words, and this is a question, is it possible that we are more likely to get better using a treatment that REDUCES DHT temporarily on the body…

Now one might argue, why not take an AR antagonist such as flutamide or RU, but this is not the answer i think because you do not want those chemicals to bind to the receptor, you just want the receptors to be processing less DHT, which seems to happen when you take progesterone…

Any other way to decrease DHT? Of course without messing up with the 5alpha reductase…

i have read somewhere, and i could be wrong, that a secondary mode of action of finasteride is that it acts on the AR receptors… And i think this is HuGE…i don’t think all our problems are cause by the 5alpha conversion, because some people have very similar sexual side effects using antiandrogens…

Some thoughts that s all…

#2

I have seen cases of RU causing PFS, I would stay away from anti-androgens and 5ar inhibitors.

I think a better bet would be to try to lower AR expression. I have a protocol I will be trying after a few weeks that an androgen receptor researcher helped me come up with. From what he said, he is able to raise AR expression too high in animals and the animal gets androgen insensitivity.

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#3

^ i was not suggesting anyone getting in antiandrogen. I actually say that explicitly.

Can you pLEASE tell us about this study/research/regimen? You got my interest. An increase in the expression of receptors that leads to insensitivity hits close to home…

#4

They have shown that by purposely and dramatically increasing AR levels/expression, rats have developed AR insensitivity like conditions. In addition they showed that raising the AR levels alone is not enough to cause this condition, you also had to have increased androgen levels. For example, the rats that were castrated and they made have high AR levels, did not develop this PFS or androgen insensitivity syndrome. Only the ones that they supplemented androgens with. This seems to corroborate Awors “Flood of DHT surging back” theory. Its not the exact same as PFS, but similar.

His first recommendation was taking an androgen antagonist to lower AR levels (Flutamide reversed this condition in some of their rats…interestingly, castration improved it as well). I am not going to touch any anti-androgens myself though, so we are going to come up with a less risky protocol to try out. It most likely will not work, but its worth a shot. I am not eligible for any of the PFS studies anyways. I wont be starting this for a few months, but I will def let everyone know any progressions. IF methylation is in play for the reason AR levels are so high in us, then it doesnt seem to me that a protocol aimed at lowering AR will work if it is not targeting the methylation factor itself.

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#5

FYI, Decitabine is a de-methylating agent. May want to mention that to your doctor.

#6

“Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells.”

ncbi.nlm.nih.gov/pubmed/21965742

Does anyone know if anyone here has tried flutamide in order to reduce AR levels?

#7

Do you have any ideas why alcohol, stress, masturbation (crash triggers) would affect AR insensitivity/methylation?

#8

My doctor recommended (He only recommended this, he said there was no risk anyway) to reduce the dosage to 1mg every second day for 2 weeks and then to 1mg every third day before quitting propecia. Is it something that Merck recommend too?
Im my opinion it makes no sense because 0.25 mg inhibit as much dht as 1 mg.

#9

Idk, there very well may be a second component to PFS being the neurosteroids. Finasteride lowers allopregnenolone way more than it does DHT, With allopreg so low it could have made us way more susceptible to a “crash” like state or breakdown. Could be why so many people crashed after a night out drinking, stress from job/relationship, illness, etc. PFS is so complex that its all just conjecture. That why donating to the foundation is so important.

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#10

The androgen insensitivity theory is fairly precise though.

  1. Increased AR sensitivity when androgens are low
  2. AR are shocked when androgens abruptly increase and react with insensitivity

None of the crash triggers should affect that. I don’t see a possible link between low allopregnanolone (which is clearly significant) and resulting AR insensitivity. I’m all ears though if someone can come up with a theory.

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#11

Moonman,

The study you mentioned (but no link?) is very very interesting. I was going to say bingo this is exactly what some of us have but the again BENS mentions a reasonable challenge to this idea, which is why our symptoms fluctuate.

If indeed we have androgen insensitivity The answer to this is difficult obviously but any theory can be equally challenged, let me try:

We do not have complete androgen insensitivity, that is for sure. But insensitive enough that even a normal level of hormones in the blood no longer causes baldness nor sexual sensation, hmmm.
But, since clearly some receptors are still working OR all receptors are working just they are less sensitive then increases in DHT binding to the receptors that is not counteracted by increases in other feminizing hormones or by a further desensitization of receptors does some good. For example, if i take 3 pills of androhard twice a day, i feel better, sexually and mentally, but this only happens when i use androhard very very rarely, like once every 3-4 weeks. If i take it 2-3 days in a row this effect goes away. Similarly stress is known to reduce T and thus DHT and alcohol reduces T but the next day increases T as the body tries to compensate for the drop (there are studies on this).

So my bottom line is that i think we have enough evidence of some degree of androgen insensitivity, but because it is not complete there are days when the conditions are good enough for us to feel almost normal. What are these conditions? Hard to say but clearly changes in T/E and DHT play a role, however had we absent androgen insensitivity it is hard to explain how a doubling of dht will not make us more sexual, in a persistent way that is.

So it is very possible that we have both, a disequilibrium in hormones and androgen insensitivity, but i think the latter is the problem, cause i think we would have managed to get back to equilibrium over a short period of time or through medications if the AR are not reacting oddly to stimulants…

my own experience: before propecia i was using RU, a flutamide like agent. One day i overdosed on this pretty badly, i had immediate exhaustion and over the following 2 weeks i had weird genital numbness that drove me crazy. Stupidly, i was not sure whether to associate this with RU or with biking induced pelvic pain. I stopped both but i continued to feel like shit. Nit wanting to neglect my hair i went back on small dose of RU thinking it is impossible for this to be the cause, and i remember that within few days everything normalized and i was again horny like hell… Had i linked the numbness at that time correctly to that RU super dose i would probably have never tried propecia…

I really really think that what moonman says supports my theory and we need to see how we can experiment with that without hurting ourselves (not with antiandrogans but maybe food). Think about it this way: more T makes most of us worse, so it is not crazy to think that less will make us probably better (it is clearly not given but one possibility, …). When i do resistance training (which increases T) my penis get numb like hell. When i go for a long long walk or long slow run(reduces T) i feel better.

Hmm…

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#12

One thing we need to understand is that serum DHT is useless. It does not function in an endocrine fashion. DHT is an autocrine hormone. ie it is produced on the spot right next to a receptor to be used right away. That is why tissues have their own (and different types) of 5ar.

So for guys who supplement DHT… that isn’t how DHT is used by the body. Although I can understand it having some effect. By supplementing DHT you could be down-regulating DHT production in the manner it is supposed to be (and is effectively) used. Then after a few days you are left with a bunch of (relatively useless) serum DHT.

Grueling exercise will stimulate the sympathetic nervous system, whereas light exercise will have the opposite effect.

I am not saying AR insensitivity isn’t the answer. But if we want to figure this out, we have to look at what we know. And the information we have does not point in that direction IMO. It should be tested for however and honestly they should be able to figure that out.

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#13

Thanks Bens, i like your scientific approach. I do not deny the fact that serum hormones are not providing the full picture but i cannot see what is the basis of rejecting this hypothesis (of receptors being desensitized). I think you are rejecting them in the basis that one some days some pfs sufferers feel almost normal, but these days could involve an abnormally high dht production or any level of hormone level or ratio that somehow compensate for the partially densensitized ARs.

I have two additional reasons:

1- we are not the only one to mess with hormone levels, body builders do it all the time, but they manage to recover, and do not experience pfs symptoms (insensitivity, hair stabilization,…). People here are here either because of 5alpha inhibitor or because of an antiandrogen (few cases). Fin is also known to have a secondary direct effect on the receptor as far as i understand.

2- the studies conducted so far on PFS have not shown a consistent difference in hormone levels between PFS and healthy, and the only one that has found something is the italian study: showing overexpression of AR!!! So if AR is over expressed and we are not managing to find a difference in hormone levels that seems to suggest that ARs are acting weird. Of course you might argue that the hormone problem is LOCAL … I am not sure if studies have tested that.

So while i agree we do not have any solid theory, i would not rule out the AR at all. And i am waiting for moon to send me a link of that paper.

#14

I am basing it on everything I know, not just fluctuating symptoms.

  1. Instigators of crashes
  2. Fluctuating symptoms
  3. Only some people say that their hair loss stops. And they may not have had significant further hair loss anyway. However, many people have their hair continue to fall out at a normal rate. Or body/facial hair growth stays the same.
  4. Bodybuilders, as you said, mess with their androgens all the time and don’t get androgen insensitivity. At least, I have never heard of someone with a similar symptom profile to PFS. What bodybuilders don’t do is mess with their neurosteroids.

In addition… people crash at different times. I crashed after 7 weeks. From what I understand DHT should’ve been long stabilized by then. There are people who crashed after 3 months. I don’t see why ARs would start to wig out after that amount of time.

The AR overexpression was in the foreskin iirc. That sounds like it could be due to something as simple as poor blood flow and low circulating androgens. Who knows. Poor blood flow seems like a fact. Obitoo from hard flaccid claims that he had hypogonadal T levels just from hard flaccid and poor blood flow.

#15

I’m glad I’ve found a current discussion on here --which is hard to do.

Because I’ve not been studying the potential sources of our problems, the best I can muster at the moment is: are you discussing whether AR gene over-expression might be the source as opposed to inadequate DHT or inadequate 5 alpha reductase?

Also, I can see “bens” discussing insensitivity above. bens, if you think that insensitivity is a good theory, then how would you account for an increase in symptoms after many months or 6 years of symptoms when a guy suddenly takes either an A) an estrogen block (product: “Inhibit E”), or he has taken broccoli extract and experienced a further permanent de-sensitization of his penile tissue, along with further shrinkage of genitalia?

I am beginning study in molecular biology and some genetics this year, so I plan on spending some time getting up-to-speed on our problems.

This site has been long-overdue for some re-organization. I found this discussion via a search on resveratrol on google; not by looking through the index.

#16

T-bone, I find that using the 'view new posts" button in the top right corner of the website the best way to find current threads.

From what I understand, the Italian study is looking at PFS from the 5ar enzyme perspective and the others are looking at it from the androgen receptor perspective. There is also a good mixture of genetic profiling, epigenetic profiling, neurosteroid and hormonal profiling, looking at nerves, etc.

#17

The progressive symptoms related to PFS seem to be physical. ie erection quality, numbness, shrinkage, etc. I think that a lot of these things can be attributed to the often progressive nature of pelvic floor dysfunction. I’ve never read about someone’s libido, brain fog, or sleep getting worse post crash.

However, I don’t think AR insensitivity is likely. Not everyone crashes after ceasing the medication. Many people develop PFS while on the drug and it just never goes away. So the proposed mechanism for AR insensitivity developing doesn’t make sense.

#18

t-bone, glad you joined the conversation. If i was not too old and too sick i would have enrolled in medical school because of this crap.

Bens was skeptic about insensitivity, it is me who was pushing it a bit. I think these conversations are useful.

you mention something VERY important at least for me. Indeed when i took small quantities of an aromatase inhibitor i felt like shit for days after. However my experience with it has been mixed. There are times when i took it and felt much better. It seems very much dose dependent.

I am not sure how that squares with receptor insensitivity, if at all!! I am not pushing this story of receptor problem, it is just that there is not enough evidence in my mind to rule it out. Indeed both studies plan to look into the receptor…

I have heard good stories about broccoli. There are bad ones too? Shoot everytime i go and buy something i hear a scary story about it. I got tribulus and before intake it i read a couple of scary stories.

#19

well, just to let you guys know I am the guy who tried Inhibit E and broccoli extract and saw his symptoms worsen.

I tried broccoli extract just this month for about 5 days only and saw my gentalia shrink even more and pretty the remainder of my glans went completely numb (but for a little bit near the urethral opening (meatus?). It would SEEM that based on my experience with both Inhibit E (2010) and with broccoli extract much more recently, the simplest explanation might be conversion of more protein into female hormones. But I really have no clue and I have to wonder why a female hormone would cause the penis to become numb. What ideas do ANY of YOU have on this? My post-fin crash happened exactly 6 years ago.

Just to make this all crystal-clear: six years ago, during my post-FIN crash, my penis and testicles shrank to their first post-FIN size accompanied by a lot of permanent desensitization all along the penis but somewhat less desensitization in the head (glans) of my penis (exhibit B). When I took Inhibit E in autumn of 2010, my penis was shrunken permanently slightly more and further densensitized (permanently)… that’s penis “C.” Now, over 4.5 years after the Inhibit E, I’ve tried the first product since then, which is broccoli extract (2000 mcg Sulfuraphane) and now found a permanent shrinkage and even further permanent desensitization of my penis (exhibit D). At this point, my junk is “colder” than it ever was, having the sensation of being run over a cheese grater and exposed to frost in the area of the penis under the prostate (the “taint”).

ALLO enhancing drugs that might not have been considered
#20

The numbness coincided with the shrinkage. Shrinkage is due to poor blood flow (or rather, dominance of the sympathetic over parasympathetic functions), which is related to hypertonicity of the pelvic floor. I don’t think that any hormone problem could simply shut off the sensory capabilities of a nerve. It seems that the numbness/sensitivity issues are related to blood flow and possible nerve impingement.

I understand that libido, etc. can increase pleasurable sensations, so there’s that. But a lot of guys can’t even feel hot/cold or pain. Or can barely feel it.

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