BAT, dutasteride, and my search for truth, Part 2 of 2

[cigafred]

I believe it was Patrick who said

“When 5alpha-reductase acts on T to produce DHT, this kicks off production of an enzyme to clear DHT from the cell. DHT has a very narrow window in which to promote growth. One of the metabolites of DHT is an estrogen - 3beta-adiol - which happens to be the natural ligand for ERbeta. When 3beta-adiol binds to ERbeta there is resistance to further growth. So, by allowing DHT production, one is also allowing ERbeta to prevent proliferation. DHT is an intrinsic factor in growth regulation. But at the point that the cancer suppresses ERbeta completely then DHT is no longer your friend. At that point, use dutasteride to inhibit 5alpha-reductase.”

So, I thought, maybe one could decide about dutasteride based on Erbeta and when it comes and goes. Welcome to my rabbit hole.

This first article begins the confusion (my caps for emphasis):

“This antiproliferative role of ERß also concurs with immunohistochemical findings in human PCa tissue samples, suggesting that ERß EXPRESSION IS LOST IN HIGH-GRADE TUMORS (42,43,44)”

BUT

“Recently, a theory of switching roles of ER during prostate carcinogenesis has been proposed, based on observations that elevated ERß protein levels are detected in castration-resistant prostate cancer cells (CRPC), whereas these levels are related to lower survival in hormone-naive prostate cancer cells (HNPC). The theory suggests that in the early phases of PCa progression, ERß presents a tumor-suppressing role and then is altered toward a tumor-promoting agent. It also proposes that ERß signaling pathway in HNPC is mediated by Serin210-phosphorylated androgen receptor [pAR(S210)], but this observation disappears with the approach of CRPC, when AR gene stimulation takes over, perhaps in relevance to the lower levels of androgen in the body. The exact cause of this switch is not fully understood and the pathway that triggers the connection between pAR(S210) and ERß in HNPC, if any exists, is currently unknown (56,57).

Indeed, immunohistochemical studies have suggested that HIGH GRADE TUMORS EXPRESS ERß (68)

ncbi.nlm.nih.gov/pmc/articl...

The Role of Estrogen Receptor ß in Prostate Cancer

And this article finds variation in the presence of ERbeta:

“These findings raise the attractive possibility that lack of expression of ERß may contribute to the initial phases of epithelial tumorigenesis. In terms of the early phases of prostate intraepithelial dysplasia, Leav and colleagues 11 found expression of ERß in low-grade prostate intraepithelial neoplasia lesions but lack of expression in cells displaying high-grade dysplasia. Thus, ERß may be expressed in the very early phases of dysplasia (low grade), perhaps to counteract proliferative stimuli but lack of ERß expression occurs, and may in fact be required, in the lesions with high-grade cytological atypia, known to be associated with invasive carcinomas.”

AND

“The finding of increased ERß in both moderately differentiated cancers and aggressive metastatic tumors is also contradictory. In essence, is ERß the good guy or the bad guy? Is its down-regulation associated with tumorigenesis and/or tumor progression or is the expression of ERß in prostate tumors of advanced stage transducing signals that favor tumor aggressiveness?

They have shown that ERß is expressed in basal cells in normal prostatic acini, it is not expressed in high-grade dysplasia, is expressed in the majority of moderately differentiated, invasive cancers whereas it is lost with increasing Gleason score. Interestingly, ERß was somewhat surprisingly expressed in androgen-independent metastatic tumors. The data provided generate more questions than they answer. In addition, one must bear in mind that the number of cases assessed is small and that the antibody has not been validated by other groups. Therefore, additional immunohistochemical studies to assess ERß expression in prostate cancer are necessary.”

ncbi.nlm.nih.gov/pmc/articl...

Estrogen Receptor ß in Prostate Cancer Brake Pedal or Accelerator?

And this paper does not help my confusion:

“In conclusion, ERß may play a significant role in prostate cell differentiation and proliferation and may modulate both the initial phases of prostate carcinogenesis and androgen-independent tumor growth. Whether ERß enhances or suppresses prostate cancer development and/or progression remains to be established.”

[and not directly relevant, but interesting]

“In conclusion, ERß suppressed the viability and migration of the PC-3 and DU145 prostate cancer cell lines and induced apoptosis. Furthermore, it reduced inflammation and suppressed the activation of the NF-kB pathway, suggesting that ERß may serve roles as an anti-inflammatory and anticancer agent in prostate cancer.”

spandidos-publications.com/...

Estrogen receptor ß suppresses inflammation and the progression of prostate cancer

Thus, thinking about Erbeta has not helped my dutasteride analysis, but I am way out of my comfort zone on this and probably missed a lot.

[jdm3]

Thanks for your sharing this analysis and thought process. I agree that it's confusing and we get mixed messages depending on the source. My conclusion is to control both DHT and E2 while off ADT drugs and with normal to high T. I was not only compelled by Friedman's book, but basically concluded that it couldn't really hurt (first do no harm) and might even help.

[cigafred in reply to jdm3]

I am thinking you are correct. Thanks.

[Hidden]

Good detail. Thanks!Lots of ifs ands and buts. Hard for me to make any conclusions.

But the balance tips for me because Dr. Bob uses duta on his SPT patients. Apparently he is having great success. And Friedman also recommends DHT reduction.

I might change my cycling just to cycle Fina and duta and see how my DHT reacts to each. Perhaps no off period. But if my PSA goes up or I have positive cancer scans I still plan on going off of 5-ARIs to see what happens. As you know I'm going to try as much as I can before going low T.

[cigafred]

Thanks for these replies, and for the replies by direct message. As per these replies, I think that the weight of evidence points to continuing dutasteride, but it is not certain and I can't get that finasteride example out of my mind.

[Shorter]

Thank you very much cigafred. I have been looking for this information for a discussion I have been having with my urologist. Although hard for me to understand it all, some of it and the links provided in the documents in this back up an argument I have been having with said urologist.

[MateoBeach]

Yes, indeed the roles of ERa and ERb seem filled with contradictions and nuance. You can probably throw out all of the PC in vitro cell-line studies on estrogen effects. It requires the stroma effects in tissues that interact with the ERs. Another element is that many of the studies did not have sufficient immunoassays to differentiate between ERB1 (wild type) and the mutated ERB2 which accounts for the altered activity of ERBs in more progressed cancers. No simple way to sort it out that I can see. It makes me question my advocating estradiol to help with the SEs of ADT. Probably OK in less progressed disease such as HSPC (maybe!). But must attend to any adverse changes in PSA control.These articles explained a lot:

Estrogen Receptor Beta in Prostate Cancer: Friend or Foe?

researchgate.net/publicatio...

And:

molmed.biomedcentral.com/ar...

[cigafred in reply to MateoBeach]

The erudition on this forum is overwhelming. Thanks.