I'm reading a book by Dr Edward Friedman The New Testosterone Treatment. I am finding it fascinating and confusing. He claims that the acting hormone for promoting Pca growth is estradiol and not testosterone at all. He makes a very convincing case for his claims.
I'm trying to reconcile this with the fact that many men on this site are using supplemental estradiol patches while on ADT or using E2 as their sole T suppressant. If Dr Friedman is correct, we should be concerned with suppressing E2 not T.
I'm sure the great brains on this site are familiar with Dr Friedman's theory. I would like to know your opinion and if any of you have applied his theory to your treatment protocol. If so, how, and what has been the results?
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What kind of studies has he done on this? I'd like to know more about it. Seems like most of the literature on this subject is kind of old. Like maybe it doesn't work.
I would recommend that you get his book and read it for yourself. It's available online. The title is: How you and your Doctor can Fight Cancer by Dr Edward Friedman
As reflected in this paper, the common consensus has seemed to be that ER alpha is a bad player in PCa and ER beta a good/neutral one. The most recent research I have seen indicates that the distinction between the roles of alpha and beta may be specific to the cell-type used in the research, (Since most, if not all, of the research is done in labs and not patients.) That would further confirm the heterogenous nature of PCa and the difficulty of generalizing about the efficacy of treatments across such a diverse patient population. All speculation on my part. But as only a single (or select few) of the many known PCa variants are used in the majority of lab research, it is important to understand the individual nature of the cells used in the research, before assuming it can be applied to your own disease state.
Ever since Charles Huggins discovered that castration could be used for palliation, many have assumed that testosterone [T] causes PCa or drives progression. Even 75 years later, treatment usually targets the androgen receptor [AR] axis, and many men believe that ADT might cure them. Palliation treats symptoms but not the cause.
The literature 20 years ago made clear that at diagnosis, the AR is usually "wild type" (normal). AR-related changes do not occur until the AR-axis has been targeted.
In contrast, by the time PCa is diagnosed alterations have usually occurred in the area of the estrogen receptors [ER]. The growth-inhibiting ERbeta has become downregulated and pro-growth ERalpha may have begun to appear.
On that basis, I felt that (following 'curative' treatment failure) there was little risk in boosting T while suppressing estradiol [E2]. I was able to use T continuously for several years.
Life Extension claim that E2 should be in the 20-30 pg/mL range for healthy men. Men make E2 from T, via aromatase. During ADT, there is not enough T for E2 to be a concern. However when E2 falls below ~12 pg/mL, there is not enough E2 for bone health. A low-dose E2 patch to bring levels up to 20 pg/mL, say, will prevent bone loss due to E2 deficiency.
When E2 is used for ADT, a massive dose is used to bring T to castrate levels. While T does not drive PCa, AR activation is required for progression. Without T, E2 cannot drive growth.
In the two instances of E2 use, estrogen dominance does not occur. I feel that the E2:T ratio is a very important treatable risk factor for PCa. With estrogen dominance, T becomes growth-permissive. An unfavorable ratio rarely occurs before later life.
Thanks for the 'share', Patrick. Esp. for the concise overview of E2 and it's interactive role with T. Your story of non-SOC success is one that I believe all PCa patients should consider long before they reach CR-status.
Many here at FPC have read Friedman's book. I had to read it several times to make sense of his theoretical framework for PCa - and Testosterone's role in it and other diseases. Like the group at Moffitt looking at evolutionary theory as a model for cancer progression, Freidman, being a PhD vs MD, would likely fall into the new category called Mathematical Oncology. Not at all a negative swipe, just a note of distinction.
Also, I encourage you to extensively explore his end notes, as there is much valuable content in there. Note also that Friedman occasionally replies here at FPC. I think we can indirectly thank Patrick for that.
Good Luck with the read. You will eventually see his logic.
Thanks to all of you for your response. My 24mo stint with adt was intended to be curative, but I am continuing to educate myself so that if I ever need to resume treatment, I will have a plan.
I am intrigued with BAT and following you guys in the shadows. I'm just trying to figure out how Dr Friedman's theories fit into all of this.
Friedman mentions Dr. Abraham Morgentaler briefly in his book and many more times in those rich end notes I referred to earlier. Morgantaler's work with Testosterone has been revolutionary and is in a related way being validated with the current use of BAT. Here is a good recent Grand Rounds Interview with him that describes his life's work related to TRT and the development of his Saturation Model for T and PCa.
Testosterone Therapy in Clinical Medicine: Interview with Abraham Morgentaler, MD, FACS, Grand Rounds in Urology
Estradiol therapy wasn't brought to my attention throughout my therapies. I have really been exposed to it on this forum (for which I am grateful for all the contributions on this subject). I really compare the current state of affairs with mental health disease (like my lifelong depression) to the state of affairs with PCa therapies. Lots of theories and lots of trials but no definitive answers on any of it. Radiation works certainly and it has been proven that ADT helps many men, and then fails for many, and then the other options "fail" or not.
What I take away from all this is the complexity of life. Each of us has more DNA that we will ever use. But some of it is turned on and off by changes in our environment, or UV, or intentional hormone changes, or just by age by unknown mechanisms. I am still reading current graduate level texts on biochemistry where many advances have been made in seeing and attempting to explore the changes in our DNA to the impact on our lives. And the interactions of one change can have multiple implications to following changes. This means that we are all unique in our bodies and our diseases and how they may be treated.
If everything were known exactly the bell curve graphs for results (actually other statistical analyses now) have wide ranges with the hope that the extremes are not too far away from the medians/averages. But they never are.
I helped build a massively complex software application, some of it was called Materials Requirements Planning) only what I helped with was for the defense industry. In that industry it is common for each model of a particular assembly (such as an F-16 jet fighter) is different than every other individual build. It was not possible to build an application for each model so it was designed with the ability to turn and turn off specific pieces of the application so it was useful for this variation in builds. It was no where near as complicated as our DNA and our human factories driven by it (and the DNA driven by our factories and environmental reactions). I was given the task along with a British co-worker to design a protocol for testing the entire application (multiple modules are interacting) and in the end we said it was too complicated to test the entirety of the application because you could no longer predict what it would do with so many factors built in to change it for airplanes, rockets, satellites, radars, etc. etc. The idea was supposedly simple but it had evolved to be impossible for a global test to certify that it would work in every case. Frustrating.
PhD's and MD's and MO's and RO's can't do this with prostate cancer either and that is only one small part of all the possibilities of diseases, environments, therapies, etc. etc. I.e. no one "correct" answer with many insisting that XYZ is the right answer and ABC is completely wrong. Witness all the back and forth on this forum and in the journals and by each doctor of whatever flavor in each country and in each specialty. Just a fact of the sheer complexity of cancer and potential therapies. Certainly some progress has been made but no one can say that one thing will apply to all things.
Apologies for my inapt digression on non-cancer things. And for the impossibility of giving short answers to any of this.
Maggiedrum - Nothing inapt about your description of your professional life's contribution to your efforts in deciphering the mysteries of cancer and human genetics/epigenetics. As a result of that experience, you have insights the rest of us do not.
As for the complexity of PCa, the paper in this post from 8 months ago, sort of blew the doors off any notion that I had that we would ever find a universally effective or curative treatment for metastatic PCa in my lifetime. The bottom line is to find the cancer early and remove or zap it before the morphological transformations get out of hand.
Spatially resolved clonal copy number alterations in benign & malignant tissue (i.e., prostate tissue)- Nature, Published online 2022 Aug 10
Your comments about the "no . . . one thing will apply to all things" is a reason to be as informed a patient advocate as you can. Many "outlier advocates" here on FPC. What is shared by them is gained via the risks they take in stepping slightly or significantly away from SOC. In every case, we can only hope the risks taken will ultimately provide the benefits they seek. Same applies to you and the rest of our fellow PCa Brothers.
Stay Positive, Be Safe, & Stay Well, Ciao - K9
PS after reading through you bio treatment history, I would suggest that an AR inhibitor (. . . lutamide) would be worth consideration, since it blocks PCa at the AR and does not block your testosterone - the loss of which cannot be good for you emotional state. I've been using bicalutamide on and off since my BCR#2 in mid-2020 (along with one 2 mos treat with lupron). Bical will usually even boost your T by as much as 50 %, which can make you feel pretty fine when compared to castrate levels. (Just beware of the man-boob booby prize and pre-treat accordingly.) I'm 75 going on 76, and like you, am looking at years ahead as gifts - provided they are of good QOL; i.e. interested in adding life to my years vs years (of misery) to my life. Like E2 for ADT, bical is still in wide use outside of USA. Justfor_ is the resident expert on using it effectively. I'm sure he would be glad to provide more info on bical use and dosing, if you want it.
Thanks cajole! As I noted above I am going to re-ask my MO next week about estrogen therapy. He completely ruled it out last time we discussed because of my very bad reaction to ADT. He said no more hormone therapies. I understand that. I do wish I had asked about it much earlier. I am also going to add using bicalutamide. We have a pretty good relationship now and since I am only on wait and see observation on a more frequent basis there will be more time to get on to those topics. I get my PSA test done tomorrow. I expect it to be still going up fairly quickly but the scans were negative for any gross tumors or bone issues. I think that is what will be the game changer for deciding on more aggressive therapy - bone radiation or dealing with a specific tumor if one is found. If significant bone invasion is seen I don't know if he will want to do a more precise PET scan or a PSMA-PET but he had said before it wouldn't be helpful in mapping out next steps in my situation.
I have learned a lot on this forum, even from the "outliers" as they get me to recheck what I think I know and may not.
Using estradiol (E2) is a double-edged sword. It will kill more PCa than ADT by itself because initially almost all PCa has lots more ER-beta than ER-alpha and high enough E2 produces ADT by shutting off T production. ER-beta helps increase the rate of cell death while ER-alpha helps decrease the rate of cell death. However, you now run into a situation in which you are thinning the herd by removing the easy pickings, namely PCa with little ER-alpha. The surviving PCa will have a huge growth advantage by increasing the amount of ER-alpha present, so continued use of E2 will eventually see an enormous growth rate as eventually you have PCa with all ER-alpha and no ER-beta. How many years it takes for this to happen will vary with the individual. Keep in mind that ER-alpha is almost totally absent in normal prostate epithelial cells, but is present at 43% for PCa cells which are Gleason 4 or 5 (note this is the first number in a Gleason score, not the total) and is present at 94% for CRPC. These percentages would be expected to be higher if the PCa is exposed to exogenous E2. See: ncbi.nlm.nih.gov/pmc/articl...
Thanks for you input Dr Friedman. I have not yet finished your book so maybe this question will be answered as I read. I understand that some drugs block T at the AR level and this approach is used in some treatment protocols ei. triple therapy etc.
Is there a family of drugs that would block E2 uptake at the ER level? I have yet to hear anyone talk about blocking Estradiol. Is total adt the only way to diminish the effect of E2 on Pca cells? Could I in any way maintain normal T and at the same time block E2?
I am facing the specter of going back on adt. I was planning that If I ever go back on adt I want to ask for E2 patches to mitigate the SE of adt. Now I'm not sure.
Hello Dr. Freidman,it is a pleasure and a privilege meeting you.Are you saying by using E2 and lowering the action on ER-alpha(which supposed to decrease the rate of PCa Cell death-and decreasing Pca cell death is not a good thing) But subsequently using E2 for long period of time eventually causes ER-alpha to retaliate or regenerate it's self more robustly and eventually decreases Pca cell even more?
Sorry that last phase was supposed to say"But subsequently using E2 for long period of time eventually causes ER-alpha to retaliate or regenerate itsself more robustly and eventually DECREASES Pca Cell DEATH cell death even more?
Actually, using E2 increases the action of ER-alpha to decrease the rate of cell death. Initially, using high E2 for ADT is more effective than ADT without E2 because initially almost all of the PCa has much more ER-beta than ER-alpha. However, continued use of high E2 will give a selective growth advantage to those PCa which have higher levels of ER-alpha. In the worst case, you end up with 100% ER-alpha and 0% ER-beta, but it is doubtful that any patient would live long enough for that to happen.
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