5ar, androgens, androgen receptors... an explanation


#1

I’m only slightly stupid generally, but when it comes to the biology of all this stuff I find I’m particularly disadvantaged. If anybody has the time or inclination, I’d really appreciate some clarification on a few things.

AR is mentioned a lot. Am I right that there are two distinct things: AR means androgen receptor, which is different to the AR in 5ar, which means 5 alpha-reductase? It’s not always obvious which one is being referred to.

An androgen receptor is something that sticks out of a cell, like an antenna, and gets a signal which tells the cell to do something. What does it tell the cell to do? Does it tell the cell to become something, or to make something?

People talk about the androgen receptor being over-expressed, because it was sort of reaching out to get more signals when the signals were reduced by the Propecia (in my case Roaccutane) - does that mean that there are too many of them? That there’s a kind of over-abundance?

…and then, when 5ar comes back online after the drugs have been stopped, is the 5ar kind of too much? Too much noise? Too much volume, because there are too many receptors picking it all up?

Is that where the misery I experience (mine is all mental) lies? I try to make a picture of it in my mind when I’m experiencing what I’m experiencing. Is it knackered, burnt out receptors…just sort of…not doing anything other than being sandblasted, is it that interface which is actually the pain?

I write all of this because in my 31 years of experience of this, I had 3 days of complete respite once, and I wanted to understand why. When I say respite, I mean a very clear and obvious draining of a swamp (this has no relevance to recent US politics). A kind of waking from an awful dream. Like a tap being turned on, and everything poisonous draining away leaving a brain that was normal. I was sitting in a Starbucks in Glasgow at the time, New Year’s Eve 2015, and I was looking around at the people sitting at other tables and the thought struck me: Jesus, this is how normal feels. It was very distinct. Jesus had nothing to do with it, it’s just a figure of speech.

I think the cause was…wait for it…drum roll…

…nettle tea.

I’d been drinking gallons of it in the days before, on a kind of intuitive hunch about a digestive issue I’d been having whilst on a retreat at an abbey on Iona.

I say an abbey on Iona. I mean the abbey on Iona. There’s only one. Iona doesn’t have room for two. So it should be the abbey, capital A, on Iona. The Abbey on Iona.

I look up nettle tea now, and find that it blocks 5ar activity - i.e. it does exactly what the Roaccutane did in the first place. How does that work?

By reducing the noise that’s shouting at the androgen receptors, is it actually giving them some kind of break?

Should I drink more nettle tea, or am I only going to make things worse? Am I going to stimulate more androgen receptors to be produced to, in their turn, get more knackered, more sandblasted and create more of this misery?

Does this offer any clues to me, to anybody, about what’s going on, and how I might ameliorate the agony of it? In all my years of struggling with this, this was the clearest incidence of something having an effect, be it negative or positive.

Is all tampering with 5ar or androgens to be avoided?

Apologies for the ramble.


#2

Amazing stuff, those temporary recoveries. It’s been a long time for me, but it gives someone a reason to hang on and believe this isn’t inescapable permanent damage. You may want to post your experience after nettle root here: A Positive Story that indicated that we aren't flawed!

…or even here: Supplement to avoid: Nettle root

No reason to put yourself down over not understanding this completely. Comprehending this stuff and being able to piece it all together to make sense of it takes a lot of time and mental strain for anyone.
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The best way I have seen to answer your question is a graphic in the “androgen receptor” wikipedia article:


Figure by Jonathan Marcus, based on an original drawing by Dr. Marianne D Sadar (Meehan KL, Sadar MD. Front Biosci. 2003 May 1;8:d780-800). [Attribution or CC BY 3.0]

Normal function of the androgen receptor. Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation § occurs before and / or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins (androgenic effect)

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  • Yes, 5-ar always refers to 5-alpha reductase (either type -I or type -II) and AR always refers to the androgen receptor(s)
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  • The AR depicted in the image is intracellular/cytoplasmic, but there are non-classical ARs encoded by different genes that are trans-membrane (stick out like an antenna, as you say) and signal through different pathways. http://www.sciencedirect.com/science/article/pii/S0303720717301120
    It basically instructs the cells to copy (transcribe) androgen-responsive genes into mRNA. The mRNA is then translated into protein product. The protein product can then influence many different characteristics of the structure and behavior of the cell.
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  • AR over-expression refers to too much AR protein being produced and/or too much AR-encoding mRNA being produced

  • Expression (expression of androgen-responsive genes as seen in the image) can refer to levels of production of proteins from genes that respond to the AR (“androgenic effect” in image), or levels of mRNA from genes that respond to the AR (also an androgenic effect)
    .

My best interpretation of the going theory of PFS is that the return of normal levels of androgens, combined with excessive levels of ARs (they were over-expressed to compensate for lack of androgens), leads to a silencing of the androgen signal to prevent a subsequent over-expression of androgen-responsive genes. I think how this silencing occurs is the million-dollar question at the moment.

This silencing of the AR signal can also lead to loss of negative auto-regulation, leading to an over-abundance of AR protein (over-expression of AR), somewhat independent of androgen levels. …again, my best interpretation.

To sum it up, we likely have over-expression of the androgen-receptor, while we lack the androgenic effect. This seems to affect different people to different degrees and in different types of tissue.


#3

Hello Dubya - thanks so much for this. If I go over it a few times, I begin to get a better idea of how it works.

And thanks too for picking up on the nettle story as one of hope - because it really was the case that my brain function returned to completely normal that day in Glasgow, even after all these years, so the system isn’t completely broken, just disregulated I guess.

I will post in the threads as you suggest.


split this topic #4

24 posts were split to a new topic: Question about sound processing disorder related to AR overexpression