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.
.
.

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)

.

  • Yes, 5-ar always refers to 5-alpha reductase (either type -I or type -II) and AR always refers to the androgen receptor(s)
    .
  • 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.
    .
  • 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.


#4

Hi Dubya,

I wanted to ask you a question since you seem to have insight into PFS.

I was on Fin for 9 years and developed some kind of sound processing disorder which is not a hearing issue since my ears have been checked neurologically and they are perfectly fine.

The doctors I have spoken to believe it has to do with how the brain processes sound coming from the ear.

If you would give it a think, do you believe this sound processing disorder could be linked to over-expression of the androgen-receptor or something else caused by fin?

My hearing does get even worse after masturbation/sex and intake of certain foods.

Thanks a lot in advance for your view on this.


#5

Hi Capello - could you describe further what you experience when you say “sound processing disorder”. I often describe my mental symptoms as a problem with processing incoming information - but it’s all incoming information, not just sound, and it causes a kind of nervous glitch in my consciousness that leads to a constant state of over-arousal. Does your problem with sound processing create an anxious state?


#6

Hi Johnnie, how are you doing?

The sound processing disorder I experience is like a feeling of mental short-circuit/exhaustion when taking in sounds, actually words to be more precise.
Glitch is a good definition of how my brain reacts to different soundscapes.
Like if there is spoken info coming to me kind of fast it triggers the glitch and I feel my brain can’t take it and it switches off the word deciphering process so i can’t hear complete sentences, for example.

Also this glitch is triggered when my brain tries to make out what is said when there is competing background noise or when people speak at the same time or when the sound quality is not clear (over the phone or television).

As for glitches for others kinds of incoming information I definitely have that too in different kinds of everyday situations, multitasking, for example, trying to write something and talking to someone at the same time puts me in that state of over-arousal and switches on some neurological mechanism that feels like heavy mental overwhelming and dysfunction.

And all this, yes, as you asked, creates a lot of anxiety repeatedly on a daily basis.

Doctors, of course, have told me I am “stressed out”, but I can tell from the dubious way they affirm this that they really don’t believe stress is the root cause in my case, and neither do I.


#7

The thing is, all these glitches get even worse when I eat the wrong kinds of foods and/or experience sexual arousal/ejaculation.


#8

That would be a hint that your glitches may be PFS-related. Many people here experience chang ein symptoms from orgasms. May Iask what food causes your glitches to worsen? It would be interesting to check whether they have anti-androgenetic properties.


#9

Hi Northern star,

Anything high in carbs, dairy, sugar/fructose, the classic foods people mention, I believe.

I’m on a high protein diet now (fish, chicken/ steamed vegetables) and it has given me relief, but the glitches persist, especially the one related to hearing.

I wonder if these glitches are a result of dysfunctional neurotransmitters? That’s the only thing that come to mind.

I’ve been reading that some people get good “mental” results from the use of amino acids, like L-Tyrosine. Do you guys think there is a bad reaction risk if I take any of those amino acids?

Should one have any specific tests taken before trying amino acids?


#10

Oh, one thing I have noticed the last month or so is that my semen has gotten less watery than before, thicker/milkier so to speak, reminds me of the pre-Fin days.
I have been on a very low carb/sugar diet for the last month, so surely there must be some connection there?


#11

I had a colon cleanse last night due to a medical check-up and the glitches we talked about subsided a lot.

Any theories on how this might be connected to AR over-expression/5ar/androgens?


#12

Dubya, another question: Does the silencing of the AR lead to inhibition of 5ar?


#13

Are the glitches still gone? What did the cleanse entail?


#14

Do you think there is any chance that the body can correct itself naturally or do you think that is impossible? Do we need to do things that reduce/refresh the AR?


#15

Hi.

The glitches are now back, but not as bad as before the cleanse.

I used something called Klyx, it’s an enema.

Also, during the last week or so, I’ve noticed that my penis has become thicker and longer, both in erect and non-erect state.

I’ve added L-Glutamine to my supplements during the last two weeks, could that be the reason?

I am currently taking zinc, B-Vitamin, D-vitamin, C-Vitamin and Magnesium supplements as well.


#16

The foods that make my glitches worsen are the ones that people here often mention:

foods high in carbs, sugar, fructose, lactose and gluten.

I basically eat cooked meat, fish, chicken, together with steamed vegetables, and sometimes some eggs and Kefir. The only fruit I can tolerate is pomegranate, which actually makes me feel better. (Maybe due to its anti-oxidant properties?)


#17

So what all are you doing these days? Basically low carb diet and vitamins/supplements? Which vitamins/supplements? I saw you mentioned zinc, B, D, C and magnesium. Anything else?


#18

What’s the consensus on zinc? I’ve heard mixed things on here. I wanted to start taking magnesium so I got a supplement that combined zinc, mg, and calcium but if everyone is anti-zinc now I’ll switch to just a magnesium supplement


#19

I’m under the impression that it can cause problems for some people but that some people supplement it without issue and think it does them some good.

Lots of people here take a multivitamin, most of which contain zinc to some degree.

If you’re thinking about supplementing, I’d suggest you do some reading, especially if you’re looking at higher amounts.


#20

Did you have someone give you the enema ?