This 2017 research paper describes the inverse enzyme conversion that takes place in the conversion of testosterone to DHT, which evolving research indicates is the real bad player in the development and progression of PCa. It also explains the mechanism of some of the current androgen drugs in common use.
I'm sure my good friend, npfisherman, will chime in with some relative commentary, but here is the paper's abstract:
Abstract
5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2.
Free access is availble for the full paper. Here is the link:
Is it possible maybe for you or npfisherman to condense the science in the article to a summary of the importance/impact of the conversion in less technical terms.
Kathie, Happy New Year to You! See the responses by Nalakrats and npfisherman below. They provide interpretation that has practical application for treatment(s).
When it come to PCa, I swim in the shallow end, but they both are diving off the high dive into the deep end!
M, I don't have time for a longer answer, but think of it sort of like the T-cell analogy in the Jim Allison post of the gas and the brake. Here the gas pedal (SRD5A1) overpowers the brake (SRD5A2) and you get cancer progression via more DHT conversion. Now reread the first three sentences in the abstract and look at the diagram at the top and see if that makes sense to you now. It's the inversion of enzyme dominance that fuels the conversion of T to DHT and ultimately also feeds the cancer.Good Luck - K9
PS Professor Fish will be along later to confirm my explanation - or correct it as necessary.
Righto! There is a growing recognition that testosterone by itself is not the major problem in PCa, but DHT. ADT reduces DHT (more or less indirectly) by blocking testosterone. If you want to understand the issue watch this video by Dr, Abraham Morgantaler
Excellent reply, Nalakrats. As always your contributions indicate many hours, days, weeks, and years of thoughtful research connecting dots that most PCa MOs seem not to even know exist. I have read most of what you posted above in separate replies over the last several years. It is helpful to see many of those individual dots connected in one place - and it serves as a reminder to all PCa patients that they need to dig deep to fully understand what seems to drive PCa once it gets out and about.
A genuine heartfelt Thanks to the Lord of the Fish & Gators of South Florida. Enjoy both your vacation from ADT and the cold of winter in the northern latitudes - & Be/Stay Well - Captain K9
That there are 5 alpha reductase 1&2 and they can convert T to DHT... 5 alpha reductase 2 is predominant in the normal prostate, but decreased in prostate cancer. 5 alpa reductase 1 is increased dramatically in prostate cancer... The preference of prostate cancer is to have 5 alpha reductase 1 to bind to AR and produce DHT. The drugs like finasteride--a type 1 blocker and dutasteride--a 1&2 blocker have been shown to decrease prostate cancer incdence/ delay development...
Bicalutamide and Enzalutamide block the AR induction of 5 alpha reductase 1, although Enzalutamide seemed to stimulate 5 alpha reductase 2 as opposed to bicalutamide...
AR controls a transcriptional regulatory switch that promotes SRD5A1 over SRD5A2 in prostate cancer cells. In return, overexpression of SRD5A1 will promote DHT synthesis and, therefore, AR hyperactivation.
I have read Nalakrats replies on this post and this is why if I take a vacation, then I will take dutasteride and arimidex-an aromatase inhibitor. I can see why he takes finasteride but the half life for dutasteride is long and slow to clear... Only one should be a plenty...
I do understand why...if 5 alpha reductase 1 is the bad player for prostate cancer, then why not double down on coverage....It makes sense... taking finasteride with dutasteride ... if overkill of the way prostate cancer progresses is wrong, then I don't want to be right...
May God watch over you and yours.. much love to you, my brother...enjoy the vacation and...post a fish picture, my man... 30's here in the WV... I need to head to Fla...
I keep looking for more information on E2 and PCA and there is very little. Other than Friedman (and Savage?) who else thinks E2 is worse than DHT and where in Friedman does it say this? I scoured that book cover to cover several times and, though he talks about E2 quite a bit, he never gives a value for maximum or optimum E2. Nor does he say E2 is worse than DHT. The only recommended target value that seems to exist is the 20+/- that Patrick has posted about, but I don't even know where that came from. Do you have some good references on E2 that I can share with my MO? I'm currently taking the dutasteride and wondering if I should be adding arimidex.
I am hoping Nalakrats will weigh in here as well, but aromatase has been shown to be a driver in PCa...Friedman felt that ERbeta was a good actor in prostate cancer and ER alpha was the bad actor... some info below:
As discussed above, ERβ can be considered a tumor suppressor, and use of its agonist may, therefore, be effective in therapeutic approaches against PC.
The question is how do you know which one is in your estrogen count?? How do you upregulate/increase ERbeta?
Is a trial using Arimidex in prostate cancer in order?? I believe so as the chance that Arimidex could be a cross over in prostate cancer is very possible... If your estrogen level is high while on vacation, some Arimidex may be in order, but Dr Sweeney is way more knowledgeable than I...
Unfortunately, there are not enough data (or at least any relevant data from trials) to get Dr. Sweeney even close to prescribing Arimidex. Not in his playbook yet. Similarly, in my consult with Prostate Oncology Specialists, they recommended the Dutasteride to control DHT (which I added), but never an aromatase inhibitor.
However, I am beginning to wish I had started some Arimidex last March when I stopped the ADT. Last time I had my estradiol measured in September it was within the normal range, but higher than our knowledgeable gurus think is prudent. And, to your point, there is also no measurement of how much ERbeta vs. ERalpha.
Time to get the hormones measured again and consider adding some Arimidex.
Wait and see what Nalakrats has to add...I have asked him to chime in here on this issue as he has done way more research into hormone therapy, and hormones than I have done I am sure...
Be well, my friend...best of luck on your upcoming test...
The more savvy members will go back and read the many posts and replies that are linked at your member pages; i.e., when you click on your member name it takes you to a profile page that has all your posts and replies. (You and Patrick are probably taking up half the HU PCa server storage between you two. And that's a very good thing!)
And new members will hopefully use the search function to search topics that take them to your posts. Also, since most posters on the PCa forums do not lock their posts to HU community members, the posts are searchable by all search engines outside HU. (That is how I found the forum in the first place. )The downside of the HU search function is that it only searches post titles/content and not post replies, which is where much of the most valuable content is often embedded.
One of advantages for members at this forum, is that we can have the sort of informative discourse that this post has sparked. While the audience is smaller, I believe that the quality of the discourse is excellent and all the participants are seemingly open-minded and more than willing to consider well-researched treatment options and add-ons. As I have posted before the Info>Understanding>Knowledge>Truth learning progression journey is the one we are on here - and in life in general. Collaborative learning is a much more thorough method to get at the knowledge we all hope will one day lead to a truth. (No matter that a particular truth may have an expiration date as more information & understanding lead to new knowledge that supplants one truth with a more rigorous new, improved one.) I'm thinking now of the long lunches you and Patrick have when you return to your summer home.
At any rate, we continue to live and learn. And the longer we live, the more chance we have to learn. In all our cases, anything we can learn that allows us to live longer gives us a chance to learn more and live even longer. I'd say that is pretty good motivation to keep our eyes and ears open to new information . . . >> >.
Thanks for your comments . . . & when it comes to fishing, tomorrow is a new day for you and the fish. Be Well - K9
Sadly, when it comes to me and you..... we do not appear on searches...courtesy of one administrator....not even an administrator on this forum... we'll just have to keep posting, following the science/information, and providing information and an alternative... It is our island of the banished... at least we have it.... Thanks HU....
While neither of us show up on member searches anywhere on HU (Thanks Mr. D), if you click on either of our member names at the top of a post or reply here (or any other HU forums where we are members), it still shows you to be a HU member and lists all posts and replies you have ever made at HU (on all HU forums). So, even though we don't exist on any member listing . . . we actually DO exist on all HU forums in which we ever participated. So, you see, we have not completely disappeared down1984's memory hole . . . At least, not yet! Perseverance has its merits in life - and also in the activity of fishing. Enjoy your Sunday & Be Well - K9
See jdm3's reply below and weigh in here please... You are the King of Hormonal Control or you and Patrick are Co-Consuls... and done more research on this than I have...I supplied some information--please pick up the ball and run it to the end zone...
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Androgen Receptor Activity (ARA) for BAT
