How does AR expression affect 5-ar activity?

General Discussion
#1

A question perhaps for the admin guys or those well versed with the AR over-expression theory:

Studies have shown that PFS patients seem to have lower level of 5-ar reduced hormones and neurosteroids.

I can’t see how this could be caused by any mechanism other than reduced 5-ar activity, especially considering the original hormones such as testosterone are at normal levels.

I was hoping somebody could explain how AR over-expression (and theoretical reduction in signalling) could result in the low levels of 5-ar metabolites which have been observed in PFS patients?

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#2

Hi Orthogs,

I am not admin, however if this might help… Short résumé:
To be sure that we are on the same page let’s remind definitions:
5AR (5 alpha reductase) is a protein with enzymatic activity. 5AR transforms TESTOSTERONE (hormone) TO DHT(hormone).

AR: Androgen Receptor - a protein that allows the binding of androgen hormone (DHT, TESTOSTERONE, ESTROGEN, etc).
I guess this protein is localized on the membrane of cells (not sure).

Explanation:
Blood results of some patients show normal ranges of hormones (TESTOSTERONE, DHT, ESTROGEN, etc). However they present identical symptoms to patients that would have reduced 5AR activity, low DHT and/or disrupted hormonal equilibrium.

If hormone levels are correct that means that enzymes work correctly = 5AR works correctly.

In this case, that means that something is wrong somewhere else in chain reaction. It might be the receptor (AR) that is not sensitive.
Why ?
Hypothesis: upregulation caused by 2 steps mechanism:

  1. Under finasteride: low DHT levels rise the number of AR to make the body more sensitive to low quantity of DHT.
  2. Stop of finasteride: quick rise of DHT levels causes hypersensitivity and body responds by shutdown of AR = UPREGULATION on DNA GENES that synthetize proteins (or part lf them) that form the AR.

It is more complex because the body cannot be considered as one same ‘‘piece’’.
Hormone levels and enzyme activities could be tissue specific. 5AR could be present in some tissues/organes and absent in others.

I hope I am not telling too much inprecisions regarding this theory.

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#3

I’m familiar with the nomenclature. I understand and entirely agree with what you’ve written above, but if fails to address my principle question - why do we see very low level of 5-ar reduced neurosteroids in PFS patients? The substrate levels are fine but the products are very low. Does the existing theory explain this?

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#4

Could you kindly link the article about this ?
Thank you !

#5
#6

The enzym 3α-HSD metabolizes neurosteroids. The induction of 3α-HSD appears to be dependent on AR gene expression. It’s in Awor’s paper from 2010.

#7

No-one has answered me why many people including me get PFS in a single day from a single finasteride pill when DHT levels go down. But I will keep asking.

#8

My free testosterone is twice the upper limit and my DHT is half the lower limit. Obviously my 5a-reductase is not working. That’s not the only problem though, as restoring DHT as I did doesn’t fix my PFS. I suspect however that if I keep my DHT at very high levels for a long time, something I am not prepared to do yet, androgen receptors may get downregulated. Notice that such an approach would go against the premise of the dominant theory about the causal mechanism behind PFS.

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#9

How come I could feel sides effects within 2 hours of taking the drug? These two hypothesis don’t support my instant adverse reaction to the drug.

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#10

I believe this may work but I think you should try L-carnitine to resensitise the receptors I also believe tribulus does the same thing.

#11

This is a good question. I have no idea.
I could speculate, but I do not know. Let’s read all existing papers on the subject. I’ll write if any hypothesis (not random but linked to already collected scientific data) comes to my mind.