A note from Richard Wassersug PhD About the use of estradiol over ADT

@overage asked this question

I raised the question because of a notice in the book Androgen Deprivation Therapy, Third Edition, by Richard J. Wassersug et.al. On page 24 there is this note on the use of estradiol in the event of castration resistance.
"There is also a concern that, with castration-resistant prostate cancer
(CRPC), there can be a change in the hormone receptors on the cancer cells. In that situation, estrogens, which may help patients in managing ADT side effects, could start to stimulate cancer cell growth. There is not much research on this, but as a cautionary note, it may be best to stop using trans-dermal estradiol if there is indication that standard ADT can no longer control the cancer."

I wrote an email to Richard Wassersug asking him this question. He replied with an extensive response, covering many issues about using estradiol instead of ADT.

Thank you for reaching out to me about that text from the 3rd edition of the ADT book. I wrote that about four years ago and would be happy to comment on why I worded it that way back then, and how I might word it now. This requires though some personal history and my perspective on how the ADT world has changed in the last few years.

For both the ADT class and the ADT book, it's been important to me that what we present is evidence based; i.e., complementary to standard oncological care and not alternative to it. Thus, for the book, I wanted to be particularly cautious and not overstate anything about transdermal estradiol (tE2), since it is not yet an approved Standard of Care. I purposefully did not mention the fact that I was on tE2 to control my own prostate cancer because it was experimental. I did not want to look like I was pitching any off-label drug treatment.

It has only been in the last two years that I have been open about the fact that I use tE2 for my own ADT. I've opened up about that now because the survival data are coming out for the PATCH/STAMPEDE trial showing tE2 is equal to or better than standard ADT for oncological control. The research team running that trial have made presentations on their survival data at three major cancer conferences over the last year and a half.

My colleagues and I in the Estradiol Initiative (see: https://estradiolinitiative.org/) have just revised a manuscript for a medical journal, where we compare patients’ interest and concerns about various forms of ADT. We collected data from >800 prostate cancer patient. The data are summarized on our website and provide a strong endorsement for tE2 ADT.

Overall, the quality of life for patients on tE2 is significantly better than for those on the standard ADT drugs. But there still are long-term questions about tE2’s effectiveness and benefits for patients, who have a large metastatic burden. It will be a few more years before those data, which are being collected by the PATCH/STAMPEDE researchers in the UK, are mature.

But back to the text you asked about..

There are two types of estrogen receptors. When the prostate cancer is hormone sensitive, the dominant receptor is the beta receptor. Stimulation of that receptor tends to suppress prostate cell growth. However, when the cancer becomes castrate-resistant and no longer needs testosterone to stimulate its growth, the dominant estrogen receptor tends to shift from the beta to the alpha form. When E2 binds to the alpha receptor, it can stimulate prostate cell growth (at least in cell culture).

Many patients do not realize is that, with advanced metastatic prostate cancer, virtually any steroid can stimulate prostate cell growth. Even the basic building block for the steroids, namely cholesterol, can stimulate prostate cell growth.

Nevertheless, I would now reword that sentence to avoid a misunderstanding that I’ve heard in recent years. What I've witnessed is many patients assuming that prostate cancer, which can be controlled androgen deprivation therapy, will eventually fail because of the ADT itself. They then think they should delay going on hormonal therapy for as long as possible.

This is not good reasoning and frankly dangerous. It does not follow that the factor that leads to castrated resistance prostate cancer is the drug treatment itself. What, in fact, is the predominant factor is the number of cancer cells. If there are few cancer cells to mutate, there is little chance of the cancer becoming castrate resistant. In contrast, if there are gadzillion cancer cells around, the chances go up that some cosmic ray will damage a chromosome in one of the cells and lead to a mutated cell that is both castrate resistant and proliferating quickly.

What many patients do not seem to understand is that the ADT did not provoke the cancer resistance. In fact, patients who start on ADT early, have less chances of the cancer becoming castrate resistant.

None of that is discussed in the book. Sadly, patients (or their partners) often ask me whether they should try E2 after one or more other standard forms of ADT have failed. By then it probably too late.

I personally feel that I have been lucky to have started on tE2 when my PSA was very low. As such, my tumor burden was low and has remained low. I have been able to get over decades of complete oncological control from tE2 alone.

So, the simple answer to your question is that, to the best of our knowledge using estradiol for ADT does not induce a shift in the estradiol receptors.

To the overall health and welfare of patients, ADT with tE2 is as good as with the standard ADT agents in suppressing testosterone. And the PATCH/STAMPEDE data show that tE2 provides as good survival as those standard ADT agents. The important point is it also provides much better quality of life.

Did I answer your question? If not, please get back to me. But if it warrants a longer discussion, I'll probably suggest that we make voice contact because I'm a very slow typist.

Yours truly,

Richard Wassersug, PhD
Honorary Professor
Faculty of Medicine
University of British Columbia

http://www.LifeOnAdt.com