Antagonism of Androgens and Retinoic Acid

General Discussion
#1

The main theme here is antagonism.

Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance

Antagonistic effects of androgen and atRA have been previously described in both the prostate, where the activity of the AR was down-regulated, and expression of the PSA gene was negatively affected after atRA treatment (39,50,51) and in lacrimal gland cells

These findings help to explain previous evidence of antagonistic effects of these hormones. For example, the opposite effects of androgen and retinoic acid in cell death are well documented (56–59). In our analysis, genes important for apoptosis have been shown to be regulated by AR and RAR, consistent with a model in which AR and RAR regulate cell death-related genes in an opposite manner.

It also implies that AR/RAR antagonistic effects are a widespread mechanism to regulate transcription within the prostate gland. These findings cast doubts on the primacy of classical androgen–AR regulation for prostate specific expression and expose the potential importance of RA not only in prostate development but also, in maintaining glandular homeostasis.

Controlling the expression of prostatic genes and antagonizing the effects of androgen is important and perhaps necessary to control prostate gland homeostasis.

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#2

Another one,

Retinoic Acid Inhibits Androgen-Stimulated Up-Regulation of Androgen Receptor Expression in Lacrimal Glands of Orchiectomized Rat

Abstract: :
Purpose: It is thought that androgens are required for normal lacrimal gland function. Androgen receptor (AR) protein expression is decreased in lacrimal glands of orchiectomized rats and treatment with testosterone restores AR expression (Rocha et al., J Steroid Biochem Mol Biol. 46:737, 1993). Treatment of rabbit lacrimal gland acinar cells in culture with all-trans retinoic acid (RA) down-regulates expression of AR mRNA and protein (Ubels et al. Exp Eye Res. 75:561, 2002). The goal of this study was to determine if retinoic acid inhibits androgen-stimulated up-regulation of androgen receptor protein expression in lacrimal glands of orchiectomized rats.

Methods: Rat lacrimal gland acinar cells in culture were treated with 10-6M RA and total RNA was probed for AR mRNA expression. Orchiectomized rats were injected with a single dose of Depotestosterone at 2.5-25 mg/kg and treated with RA at 20 or 50 mg/kg/day by gastric gavage. After 7 days lacrimal glands were removed, AR protein expression in frozen sections was determined by immunohistochemistry and image analysis, total RNA was probed for AR mRNA expression and serum testosterone was measured by ELISA.

Results: As in rabbits, RA down-regulates AR mRNA in rat lacrimal acinar cells in culture. Orchiectomy decreases serum testosterone to 17 ng/dl, compared to143 ng/dl in normal rats, and reduces the number of lacrimal acinar cell nuclei expressing AR to <30% of normal. Serum testosterone ranged from 62 ng/dl after a 2.5 mg/kg dose of Depotestosterone to 319 ng/dl after a 25 mg/kg dose. Over this range of testosterone doses, AR expression in lacrimal gland nuclei was restored to 60-100% of normal. Treatment of orchiectomized rats with RA (20 or 50 mg/kg/d) simultaneously with testosterone (2.5 mg/kg) prevented restoration of lacrimal gland AR expression and significantly reduced AR mRNA expression.

Conclusions: A pharmacologic dose of retinoic acid inhibits AR expression in lacrimal gland acinar cells in vivo, as well as in vitro. This agrees with data from other organs, such as prostate and sebaceous glands, and indicates that effects of retinoic acid and testosterone are generally antagonistic. The implications of this observation for lacrimal gland function in health or disease are unknown, especially since AR expression is not completely inhibited; however, it is suggested that retinoic acid may modulate effects of testosterone in the lacrimal gland.

^Not that this is right but going back to p.acnes being predominant in sebaceous glands, its possibly capable of both metabolising androgens and upregulating or increasing the expression of AR.
This could also include the prostate and meibomian gland.

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#3

Really interesting that a metabolite of Accutane suppresses the feed-forward effect of androgens on AR in these cells. I wonder if RA could actually reverse the feed-forward effect in a paracrine or autocrine manner in cells where this control mechanisms is otherwise active.

Damn the abstract for being so abstract about it. …No full text available.

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#4

One question would be if there’s any positive role for retinoic acid in PFS at this point.

AR/RAR antagonistic effects are a widespread mechanism to regulate transcription
and antagonizing the effects of androgen is important and perhaps necessary in maintaining glandular
homeostasis.

This post is awaiting approval?

#5

Difficult to say. Direct AR antagonists have been tried by some on this forum without any long-term success that I’m aware of.

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#6

Could this be why people go bald after accutane with relatively low testosterone?

Watched a documentary about a recovering heroin addict the other day, didn’t realise there was so significant long term side effects due to the body switching off.

So are we at risk of prostrate cancer if AR expression is increased due to a changed environment?

#7

One goes up, one goes down.

Spermatogenesis in the vitamin A-deficient rat: possible interplay between retinoic acid receptors, androgen receptor

In order to understand the mechanisms of retinol action on the testis, testicular retinoic acid receptor alpha, beta(RAR alpha and beta), androgen receptor (AR) and inhibin alpha-subunit were studied in normal, vitamin A-deficient (VAD) and vitamin A-supplemented rats by immunohistochemistry and immunoblotting. Compared to the normal testis, expression of 110 K AR was up-regulated by vitamin A withdrawal, whereas 51 K RAR alpha remained unchanged. An additional 55 K RAR alpha signal was observed. Readministration of retinol caused a marked decrease of AR in the VAD testis. By 24 h, AR declined to below the normal level. Although the 51 K RAR alpha signal remained unchanged, the 55 K band was slightly up-regulated at 6 h after retinol administration. A 51 K RAR beta protein was seen in the VAD but in not the normal testis. The intensity of the 51 K RAR beta band remained constant before and after the administration of retinol, but it had a slight up-shift at 6 h after retinol injection, suggesting post-translational modification of the receptor. The inhibin alpha-subunit of 18 K protein was undetectable in the VAD testis and increased to above normal level at 24 h after retinol administration. Immunohistochemically, nuclear AR immunostaining was more intense in the VAD testis than in the normal testis. The intensity of immunostaining declined in all AR-positive cells after the injection of retinol, but the decrease was more evident in Sertoli than in other cells. At 24 h after retinol the immunostaining was undetectable in most Sertoli cells. The regulation of the inhibin alpha-subunit by retinol in the cytoplasm of Sertoli cells detected by immunohistochemistry was correlated to the results in immunoblotting. These results suggest a possible interplay between retinoids, androgen and inhibin signalling systems in Sertoli cells in the regulation of spermatogenesis during retinol action.

Regulation and perturbation of testicular functions by vitamin A.

Livera G, Rouiller-Fabre V, Pairault C, Levacher C, Habert R.Reproduction. 2002 Aug;124(2):173-80.PMID: 12141930 Review.

#8

Pretty interesting read. Fins on one of the lists.

The role of hypothalamus-pituitary-adrenal (HPA)-like axis
in inflammatory pilosebaceous disorders

Finasteride
Blocks conversion of testosterone to DHT
Reduces sensitivity of PSU to androgen stimulation
The pilosebaceous unit (PSU) consists of a sebaceous
gland (SG) and an associated hair follicle

**Isotretinoin **
Reduces skin androgen receptor expression
Suppresses DHT production
Induces sebocyte apoptosis
Reduces facial cutaneous blood flow
Induces sebocyte apoptosis
Reduces serum levels of pituitary hormones
Reduces hepatic synthesis of IGF-1

I would also say if there are all these natural substances that are capable of decreasing AR expression, there has to be some that do the opposite as well.
Once again bacteria and our own genes make the most sense as to what would be sustainable or could play a protective role.

#9

Might go something like this…

Ar reduced till retinol reduced.
Ar increased above normal due to lack of retinol.

But I get the idea you may think Ar is decreased now, why?

#10

I think I posted this before, maybe a role for retinoic acid metabolism.
Here is an exception looking at a retinoic acid related gene that is actually driving AR expression in this study. They state its acting upstream of the AR gene.
Notice that first line as well.

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

https://ucdavis.pure.elsevier.com/en/publications/ror-γ-drives-androgen-receptor-expression-and-represents-a-therap

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

I would still more so consider retinoic acid as a general antagonist to the AR gene based on other studies.

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#11

Thanks for the studies @guitarman01. I am going to read them when i have the free time. May i ask from what you gathered for years of research, would you say PAS is tissue spesific AR damage rather than sytemic endocrinal damage which can affect the whole bodily development?

I am afraid if PAS damaged my height or shoulder bone growth etc. My doc said if it did affected the T levels, we may have ended up the least version of our genetical potential during puberty. :frowning: The hell…

Do you also have any idea if PAS can cause persistent low GH levels? Or GH receptor damage? Can you share your own results too please? Mine is all here. 212 igf-1 at 21.

My T levels never saw the good 700’s. But that may be due to lifestyle choices, bad sleep, no exercise, drinking alcohol a lot on every weekend… Stupid me. At 17 i had like 460 of T at 19 they were 550 but i felt actually worse at 19, proably due to prostate inflammation going slowly worse and worse. Im eager for your answers, cheers.

#12

idk man, your always asking me questions I dont have the answers to. Like I said before I took a full course of Accutane before I was even in high school. Do I need to be any taller? No. Im 6’1. Could I have been taller? Who knows. As far as growth and development, yes it could maybe have an impact if a person was still growing and developing. My own Dr. even muttered that before prescribing me Accutane.
“Your still growing.”
That is pretty low T at that age.
Why were you even getting your T tested at that age?
How old are you now?
It is funny though, I almost feel like Im talking to the guy from twin peaks. Funny what a little avatar can do. That and you almost had the full cast of guardians of the galaxy on here.

I would say my other self that never took Accutane especially at that age is probably better than me.
Thats a pretty good what if game.

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#13

I wonder if the confusion exists due to estrogen receptor changes as well.

Just saying AR might go up with ER so it may look like AR is reduced but it isn’t.

Something to think about.

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#14

Marginal Vitamin A Deficiency Affects the Expression Levels and Localization of Retinoic Acid Receptor and Retinoid X Receptor in Rats Meibomian Gland

#15

Well im not sure 460 is a bad T level for a 17 year old. I saw many age related charts. 400’s was normal in that range. It usually peaks around 18-20 i think? Was 460 really low for me at that age? Maybe thats what my problem is, gonadrotopin damage? Thanks.