DHT / Avodart

[pjoshea13]

New study below [1].

There have been some negative posts regarding the potential benefit of Dutasteride [Avodart] against PCa.

Dr Myers used Avodart in men on ADT who nonetheless produced significant levels of dihydrotestosterone [DHT]. (The true target of ADT is DHT - not testosterone [T].) Myers used blood tests to monitor DHT.

My concern with DHT is that it might be made within cancer cells. Normally, DHT is made from T. However, there are alternative pathways not dependent on T. A blood test will not be helpful in identifying intratumoral DHT.

In the new study:

"Meta-analysis was performed with 9 cohorts (1093 specimens) from Gene Expression Omnibus, 16 cohorts (933 specimens) from Oncomine and the TCGA cohort (550 specimens)."

"We found significant up regulation of 5α-reductase type 1 and type 3 in both primary and metastatic PC, together with the down regulation of AKR1C2 in primary PC, contributing to the high intratumoral DHT levels."

Dutasteride inhibits all three isoforms of 5α-reductase (Finasteride only inhibits types 2 & 3.)

... more below.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/317...

J Steroid Biochem Mol Biol. 2019 Nov 26:105559. doi: 10.1016/j.jsbmb.2019.105559. [Epub ahead of print]

Meta-Analysis of steroid-converting enzymes and related receptors in prostate cancer suggesting novel combined therapies.

Zhang WF1, Li T2, Lin SX3.

Author information

1

Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University, 2705 Boulevard Laurier, Quebec City, Quebec G1V 4G2, Canada. Electronic address: [e-mail].

2

Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University, 2705 Boulevard Laurier, Quebec City, Quebec G1V 4G2, Canada; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China. Electronic address: [e-mail].

3

Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University, 2705 Boulevard Laurier, Quebec City, Quebec G1V 4G2, Canada. Electronic address: [e-mail].

Abstract

Androgen receptor (AR) signaling is essential for prostate cancer (PC) progression and treatment. Experiments have demonstrated that the intratumoral androgen levels are not affected by circulating androgen levels, but rather modulated by local steroid-converting enzyme activities. The expression modulation status of human steroid-converting enzymes and nuclear receptors are of great promise to identify novel therapeutic targets. Meta-analysis was performed with 9 cohorts (1093 specimens) from Gene Expression Omnibus, 16 cohorts (933 specimens) from Oncomine and the TCGA cohort (550 specimens). We found significant up regulation of 5α-reductase type 1 and type 3 in both primary and metastatic PC, together with the down regulation of AKR1C2 in primary PC, contributing to the high intratumoral DHT levels. The expression of AR in metastatic PC was up regulated, indicating the importance of AR signaling in the progression of this cancer. The down regulations of HSD11B1 and NR3C1 in primary and metastatic PC may diminish the anti-inflammation and anti-proliferation effects of glucocorticoids signaling. Furthermore, the decrease of progesterone receptor (PGR) expression in primary and metastatic PC was also observed, relieving the suppression effect of PGR on PC proliferation. The clinical evidences of the remarkable expression modulation of steroid-converting enzymes and receptors in PC may indicate novel combined treatment against this highly incident cancer.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS:

Androgen Receptor; Microarray Analysis; Prostatic Neoplasms; RNA Sequencing

PMID: 31783154 DOI: 10.1016/j.jsbmb.2019.105559

[cigafred]

An important find IMO, thank you.

[Magnus1964]

Extremely interesting. This calls for research.

[larry_dammit]

Guys beware. I was on Avadart for several years prior to my stage 4 cancer. All the Avadart did was artificially lower my PSA and mask the results until it was to late. March of 16 my PSA started up ,by August of 16 I had full blown stage 4. If I had not been on Avadart my doctor could have seen the uptick early enough to catch the monster as I was going to see him every 6 months .😡😡. Hating this Monster

[pjoshea13 in reply to larry_dammit]

But Larry, the fault was with your doctor, not Avodart.

-Patrick

[dbrooks_h in reply to pjoshea13]

So does avodart help destroy PC cells!

[pjoshea13 in reply to dbrooks_h]

Avodart helps to deprive advanced cells of DHT. i.e. in cells that have found a backdoor way to to make DHT. (This is less likely if on Abiraterone.)

Can Avodart "destroy PC cells"? Only in so much that Avodart can plug a hole in ADT-based therapies.

For men not on ADT, Avodart can help ensure that DHT access is limited.

-Patrick

[dbrooks_h in reply to pjoshea13]

Thanks for all you do here, your input is very appreciated and a special thanks for breaking it down even more to make it clearer for me and maybe others who might be a little challenged with medical terminology.

[Break60 in reply to pjoshea13]

Patrick

I was on dutasteride but recently stopped thinking no benefit based on clinical studies pointed out by TA. I’ve been on estradiol patches since Feb with great results. I wonder if dutasteride would be helpful while on estradiol?

Bob

[pjoshea13 in reply to Break60]

Bob,

Estradiol [E2] at very high levels shuts down testosterone production in the gonads, but does not target adrenal-related or PCa-related androgen production (you would need Abiraterone for that.) So, it is possible that long-term use of E2 might select for cells that become able to produce DHT. IMO

Note that the study very likely did not include tissue from men who had used E2.

-Patrick

[Break60 in reply to pjoshea13]

Thanks Patrick. So taking dutasteride might help but won’t hurt in your opinion?

[pjoshea13 in reply to Break60]

IMO

[Hidden]

I'm on high T and take dutasteride and finasteride (and an AI as needed to keep estradiol in 15-25 pg/ml range).

Do you know of anything that reduces DHT production in cancer cells?

What is your take on progesterone? (according to this article it is down-regulated in cancer cells)

[pjoshea13 in reply to Hidden]

You asked: "Do you know of anything that reduces DHT production in cancer cells?"

Avodart should do that. The path to DHT requires 5α-reductase.

Also: "What is your take on progesterone?"

Abiraterone [Zytiga] targets steroidogenesis high up at the pregnenolone/progesterone level. There are only a few steps from progesterone to DHT, so I wouldn't use a progesterone supplement - LOL.

But the role of the progesterone receptor [PGR] puzzles me. I have never viewed an upregulation of PGR in PCa as being a good thing, but the authors evidently believe that PGR is desirable:

"... the decrease of progesterone receptor (PGR) expression in primary and metastatic PC was also observed, relieving the suppression effect of PGR on PC proliferation."

But from 2018 [1]:

"... Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone’s role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. Protein expression was evaluated through immunohistochemistry, in stromal and epithelial tissue. Associations between receptor expression and clinical data were considered using statistical survival analyses. Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0, 95% CI: 1.45–2.76, p < 0.001) and clinical failure (HR: 2.5, 95% CI: 1.29–4.85, p = 0.006). These findings are in agreement with our previous investigation on pan-PGR, indicating that the observed negative effect of PGR is represented by PGRB."

-Patrick

[1] nature.com/articles/s41598-...

[Hidden]

Dr. Bob?

[Hidden]

That's what I'm doing. Had an intake with them earlier this week. Dr. Eshaghian.

[Hidden]

I think so. He just shares the practice with Dr. Eshaghian. No real change in philosophy as far as I can tell.

[hansjd]

Patrick, I’m not sure I understand your post re the implications of taking Avodart . My brain is just not processing the intricacies of it all very well.

If you are on ADT is it beneficial to also take Avodart / Dutasteride to lower the production of DHT? Also if the Prostate is still intact and enlarged would taking it help to lower the PSA to a level that more accurately reflects the state of the PC, assuming that some of the enlargement is due to BPH.

This is something I’ve been wondering about for some time, but the MOs I’ve seen don’t think it’s necessary to take it. If you could clarify things a bit more, I’d really appreciate it. As always thanks for your great posts.

[pjoshea13 in reply to hansjd]

Hans,

Research has shown that PCa cells can progress via a path that includes non-standard DHT production. ADT can induce that behavior. How frequently does that occur? I don't know. But some of us feel it is prudent to use Avodart to inhibit production.

In 2017 there was a paper [1]:

"A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer"

In theory, Abiraterone targets all androgen production (gonad, adrenal, PCa cell), so why would the researchers figure that Dutasteride [Avodart] would help?

"Dutasteride is a type I and II 5-α reductase inhibitor which prevents the conversion of testosterone to DHT, a more potent androgen that has the highest binding affinity for the AR. Studies have demonstrated that type I 5-α reductase expression is increased in both primary prostate cancer and CRPC (10). Although the role of 5-α reductase inhibition in the prevention and treatment of prostate cancer has been controversial, combination of CYP17A1 and 5-α reductase blockade is hypothesized to result in more complete blockade of androgen biosynthetic pathways (11, 12). More complete androgen synthesis blockade through this multipronged approach could provide greater clinical benefit than solitary pathway inhibition. "

"We ... found that substantial levels of DHEAS persist despite treatment with abiraterone. This is consistent with prior data from our group in 2 neoadjuvant studies investigating preoperative intense androgen blockage in which DHEAS levels persisted at 10% to 30% of baseline levels at prostatectomy (17, 30). In the neoadjuvant abiraterone trial, serum DHEAS levels remained in the 20 μg/dL range (17). These levels may provide a depot of androgen precursors that can be transported into prostate cancer cells by solute carrier organic anion transporters (SLCO) transporters, unconjugated by steroid sulfatase, and converted to testosterone and DHT by steroidogenic enzymes to drive canonical AR signaling."

"Interestingly, the addition of dutasteride resulted in a 2-fold increase in serum abiraterone, which may reflect decreased abiraterone metabolism by 5α-reductases."

***

You asked: "Also if the Prostate is still intact and enlarged would taking it help to lower the PSA to a level that more accurately reflects the state of the PC, assuming that some of the enlargement is due to BPH."

BPH noise undermines the usefulness of the PSA test, by itself, for screening. However, by plotting a graph of PSA results, one can readily spot an upward trend, IMO.

As larry_dammit has pointed out, by removing BPH noise, Avodart might lead to a delay in diagnosis if the doctor isn't on the ball.

-Patrick

[1] clincancerres.aacrjournals....

[PhilipSZacarias in reply to pjoshea13]

Hello Patrick, Thank you for posting and your comments. Although I am not yet on abiraterone, I was able to convince my urologist-oncologist to prescribe a reductase inhibitor along with this drug - in his view it won't do anything but not harm as well. In contrast, I have not been able to convince him to prescribe Avodart during my Lupron phase. Cheers, Phil

[MateoBeach in reply to pjoshea13]

This is very interesting Patrick. First, for the confirmation that DHEAS levels remain significant even on abiraterone. So the 5-Alpha reductases (especially dutasteride) could be important in this setting if it is able to block androgen activation intracellularly within the prostate cancer. I assume this is what they meant by "steroidogenic enzymes" and not some other pathway.

I had not considered possible benefit via reduced androgen signaling by DHT while not on ADT as Nalakrats does on his off-ADT "vacations".

[curious-mind1]

HI Nal,

I'm curious, what is the advantage of taking both Avodart and Proscar?

Thanks!

Art

[EdBar]

I’ve been taking Avodart for nearly 6 years now per Snuffy Myers. I was on triple ADT most of that time, recently stopped taking Xtandi, now just on Lupron and Avodart along with Metformin and estradiol patches -1 every 3 days for ADT SE’s. PSA remains undetectable for 5+ years now.

I now see Dr. Sartor and he has no problem with Avodart and he’s not shy to speak up about a medication or supplement if he disagrees with it. He recommended I stop Xtandi after taking it for 4+ years due to adverse SE’s and the fact that PSA has been undetectable.

I’ll stay the course I’m on unless directed to make a change by one of the docs on my healthcare team.

Ed

[svzoe]

There have been some legal issues with Avodart used by some with adverse effects.

[Rexwaterbury]

How about those of us who have mCRPC and have failed xtandi and zytiga? Would Avodart be beneficial in that subset of patients?

[MateoBeach]

Most wise friend: I assume you meant both "5-Alpha reductase inhibitors" dutasteride and finasteride, and not both "aromatase inhibitors". [There are three aromatase inhibitors: anastrozole, exemestane, and letrozole.] Just clarifying. I used dutasteride for nearly 5 years combined with bicalutamide as an alternative ADT regimen that does not require castrate T levels, hence better QOL profile.

[Hidden]

99th percentile for age here, i.e. total T of 924 @70yrs.

[Hidden]

This is what the doc noted: " From all the women that you will pick out there, keep one for me". Seriously now, my biological control mechanisms have gone crazy.