Downregulation of androgen receptors.

[Tyler81]

This article talks about down regulation of androgen receptors.

It looks like E2 may indeed play a part in this and i wonder if my TRT over the years hasnt been AS effective because i use no E2 control and I have experienced down androgen down regulation of some kind.

Cause the gel definetly aint working like it used to which is why i want to come off. And even injections didnt work that great (i did use an Ai for a month or so but it didnt seem to help much)

"Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels"

Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens. - PubMed - NCBI

 

[Tyler81]

"It can even get worse... because high levels of estradiol can cause the downregulation of androgen receptors. This means that your body may respond to higher levels of estradiol by creating fewer androgen receptors as cells are replaced in normal regeneration. In other words, not only does estradiol block the available androgen receptors, it causes your body to produce fewer of them in the future! This is one reason why raising testosterone levels may not have any immediate effect. It may be that your receptors have downregulated and so you'll need to lower estradiol and increase testosterone in order to get your body to upregulate again and this takes time."

 

[Tyler81]

Estrogen down-regulation of androgen receptors in cultured human mammary cancer cells (MCF-7). - PubMed - NCBI

Estrogen down-regulation of androgen receptors in cultured human mammary cancer cells (MCF-7).
Stover EP, Krishnan AV, Feldman D.
Abstract
Estrogens and androgens are well known to exert opposing effects in several tissues. In this study, we explored the possibility that there might be a direct antiandrogenic effect of estradiol on human breast cancer cells (MCF-7). Since the biological activity of androgens is mediated by specific androgen receptors, and because the abundance of androgen receptors in target tissues is thought to be rate limiting for androgen action, we examined whether estradiol regulates the quantity of androgen receptors in MCF-7 cells. Cells treated with 2.6 nM estradiol exhibited markedly lower levels of cytoplasmic androgen receptors, measured by [3H]5 alpha-dihydrotestosterone ([3H]DHT) binding, compared to levels in cells receiving ethanol vehicle alone. The effect was time dependent, and 6-day treatment of cells with estradiol resulted in an 80% reduction in [3H]DHT binding. Occupancy of androgen receptors by estradiol did not account for this difference. Cytosol competition studies demonstrated that the androgen receptor in MCF-7 cells possesses an approximately 125-fold lower affinity for estradiol than for DHT. In addition, tamoxifen, a nonsteroidal estrogen antagonist, blocked the estradiol effects on [3H]DHT binding. These latter studies support the hypothesis that this estradiol action is mediated by the estrogen receptor. Equilibrium binding studies indicated that the observed decrease in [3H]DHT binding after estradiol treatment was due to an absolute decrease in the number of cytoplasmic androgen receptors per cell. The estradiol-mediated reduction in androgen receptor content was dose dependent; a 50% reduction in androgen receptor number was observed after 6 days of treatment with 2.6 X 10(-11) M estradiol. Additional experiments revealed that MCF-7 cells exhibited a time-dependent increase in androgen receptor content when estradiol was withdrawn; continued estradiol treatment prevented this rise in receptor content. Moreover, androgen receptor levels began to decrease from the point when the ethanol vehicle added to the medium was replaced with 2.6 nM estradiol. In summary, estradiol treatment caused a reduction in androgen receptors, and estradiol withdrawal lead to a rise in androgen receptors. We believe that these results provide a mechanism whereby estradiol may directly antagonize androgen action. Conversely, estradiol withdrawal may potentiate androgen action by allowing androgen receptor levels to rise. This hypothesis may help explain the basis of the estrogen/androgen ratio as a predictor of sex steroid response.

 

[Docd187123]

You posted two studies that don't support your opinion. One was done on castrated cats and he other on in vitro mammary cells. We're primarily concerned with muscle and bones not cultured human mammary cells with cancer or cats. Dr. Scally has posted several times about how androgen receptors up regulate in the most important tissues, muscle and bone, with AAS administration.

 

[Tyler81]

I would need to see studies on that. Estrogen downregulates androgen receptors and a portion of T is aromatized to e2.

So it's safe to assume people who are prone to aromatization would experience down regulation on TRT.

 

[Michael Scally MD]

Hypotheses generating is an excellent exercise. However, science is much harder and requires a much higher burden of proof. This idea has many problems, but the biggest is there will never be support due to the issue being so complex.

 

[Docd187123]

I would need to see studies on that. Estrogen downregulates androgen receptors and a portion of T is aromatized to e2.

So it's safe to assume people who are prone to aromatization would experience down regulation on TRT.

No it would not be safe to assume that. You've yet to show what level of aromatization or E2 levels are needed down regulate the androgen receptor. You've yet to show which androgen receptors down regulate bc you've only shown it happening in cats and cultured human cancer cells. And you've yet to understand how AAS administration upregulates this.

 

[Tyler81]

No it would not be safe to assume that. You've yet to show what level of aromatization or E2 levels are needed down regulate the androgen receptor. You've yet to show which androgen receptors down regulate bc you've only shown it happening in cats and cultured human cancer cells. And you've yet to understand how AAS administration upregulates this.

I have yet to show nothing. Lol. I am just going by studies that have shown that ESTROGEN DOWNregulates androgen receptors.

I have yet to see a study that shows that testosterone UPregulates receptors.

If you have one please post it.

 

[Docd187123]

I have yet to show nothing. Lol. I am just going by studies that have shown that ESTROGEN DOWNregulates androgen receptors.

I have yet to see a study that shows that testosterone UPregulates receptors.

If you have one please post it.

In other words youve yet to show anything significant to back up your statement about TRT and down regulation bc of the key elements missing I pointed out.

Anyway here's a few for you, and one specifically points out castration can down regulate AR expression on its own which further can explain your castrated cat study.

http://press.endocrine.org/doi/full/10.1210/jc.2004-0084

Pharmacological doses of testosterone upregulated androgen receptor and 3-Beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase and impaired le... - PubMed - NCBI

Up-regulation of the levels of androgen receptor and its mRNA by androgens in smooth-muscle cells from rat penis. - PubMed - NCBI

Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. - PubMed - NCBI

Testosterone up-regulates androgen receptors and decreases differentiation of porcine myogenic satellite cells in vitro. - PubMed - NCBI

 

[Tyler81]

The second study;
"The upregulation of AR and 3βHSD in testosterone-impaired Leydig cells steroidogenesis could be the possible mechanism that maintain and prevent loss of steroidogenic function."

The last study shows upregulation within 24 hours but what about long-term studies?

At least you posted some studies.

It doesnt change the fact estrogen down regulates AR.

 

[Docd187123]

The second study;
"The upregulation of AR and 3βHSD in testosterone-impaired Leydig cells steroidogenesis could be the possible mechanism that maintain and prevent loss of steroidogenic function."

The last study shows upregulation within 24 hours but what about long-term studies?

At least you posted some studies.

It doesnt change the fact estrogen down regulates AR.

Once again, you've only shown that in castrated cats and cultured cancer cells, not to mention the fact that those studies must be REPLICATED AND OEER REVIEWED for them to be a "fact" as you claim them to be.

It's a simple Google scholar, pubmed, medline, etc search if you want to look for long term studies but you didn't post any either.

Lastly, another thing you're failing to realize, is this topic is complex like Dr. Scally mentioned. One factor that I doubt you've even considered about this issue is that it is tissue specific....

 

[Tyler81]

Tissue specific?

 

[Docd187123]

Tissue specific?

Yes. Think of nolvadex for example. It's a mixed agonist/antagonist. Whether it's an agonist or antagonist depends on the tissue in question. In breast tissue ERs, it's an antagonist but on lipid profiles (not really tissue but used as an example), bone tissue, uterine tissue, etc it's an agonist. There's also varying degrees of sensitivity and efficacy depending on the tissue in question.

 

[dutchez7]

This article talks about down regulation of androgen receptors.

It looks like E2 may indeed play a part in this and i wonder if my TRT over the years hasnt been AS effective because i use no E2 control and I have experienced down androgen down regulation of some kind.

Cause the gel definetly aint working like it used to which is why i want to come off. And even injections didnt work that great (i did use an Ai for a month or so but it didnt seem to help much)

"Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels"

Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens. - PubMed - NCBI

I have had similar problems as you described. Gel worked at first then I developed some type of tolerance so I went on injetions. I was taking 42mg test-e every 5th day. I think this was too much bc about three years into it I started developing tolerance again. Have you found a resolution to your problem? I have found a work around but it's not healthy long term. I am eager to speak with someone else who has experienced the tolerance problem on TRT.