The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males

[Aardvark4]

Hi guys,

I'm in the process of reading this so can't comment on it's usefulness, but read enough to know it would be of interest to many here.

academic.oup.com/jes/articl...

[Broccoli24]

very interesting… thanks for posting. E2 supplementation could really improve QoL for so many in the right circumstances.

[JohnInTheMiddle]

Super thanks for posting this high quality article, Aardvark. There have been a few discussions from time to time on this forum on the topic of low-dose transdermal estradiol for estrogen add back for men with metastatic prostate cancer.

The possibility of major contributions to ongoing health is the important context. Especially because up to a third apparently of men with metastatic prostate cancer die from cardiovascular and heart disease associated with therapy.

It is strange however that the front line community of clinicians supporting men with metastatic prostate cancer appears to be quite averse to even exploring the double loss of testosterone and estrogen.

And why do we have bone strengthening drugs, which are kind of scary to my mind, regularly proposed? Not because of testosterone, or cancer, but because of the drive-by side effect of estrogen suppression. (For newbies: estrogen is made from testosterone in a man's body.) Indeed many of the worst impacts on quality of life under a regime of metastatic prostate cancer therapy seem to be as a result of very low estrogen, including osteoporosis, cardiovascular risks, possibly brain fog etc etc. - and not so much directly as a result of the cancer itself or low testosterone.

Things are happening though! The famous and newly released PATCH study supports the safety of transdermal estradiol. This solves the issue of blood clots associated with taking estradiol by mouth.

But what we are talking about here is not the subject of the patch study - which is high-dose estradiol as a full replacement for all our ADT therapies. The topic here is low-dose transdermal estradiol for the purposes of estrogen add-back. And there are studies and advocates that claim that this is just an easy fix. Get someone to prescribe you transdermal estradiol and you will address serious side effects.

I haven't done this yet because I'm very concerned. From what I have learned the endocrine hormonal feedback loops in the body are crazy complex. And I'm concerned that in some weird way that doing transdermal estradiol add-back would end up supporting cancer progression.

Here are some things to think about. Specifically, estradiol binds to the two (for all intents and purposes) estrogen receptors found in so many places in the body: ERα and ERβ. Estradiol is an estrogen receptor agonist.

Here's where it gets tricky though. The two estrogen receptors are not equal. Binding to and activating ERα can be a risk because it is said to be associated with promotion of prostate cancer progression. On the other hand, binding to and activating ERβ is said to drive prostate cancer suppression.

And estradiol? It binds to each of the estrogen receptors more or less equally. It will be agonizing both the good receptor and the bad receptor. So as you see, this is complex.

Interestingly the supplement Genistein, which is a phytoestrogen extracted from plants, mimics estradiol (like so many things) - but apparently binds preferentially and significantly to the good ERβ over the bad ERα. (This rate of binding is still at a significantly lower level than with estradiol itself.) Genistein is widely available in health supplement stores.

I haven't started on Genistein. The idea of genistein as a useful supplement however is intellectually interesting.

1. Could Genistein be helpful in terms of estrogen restoration?

2. And could Genistein not only be safer because of its preferential binding, as an agonist of ERβ, but also even contribute to delay of progression and development of resistance?

3. But other questions aside, is the strength of the Genistein agonist capability too weak to have any useful effect, in any conceivable normal dose?

4. And then there's all the other concerns with supplements, such as cost, absorbability, safety and contamination, etc etc.

It will be great if any readers who are knowledgeable in these topics could suggest ways of thinking about the possibility, safety and value of estrogen restoration for men under ADT therapy for metastatic prostate cancer.

I'm coming up soon to my 3-year anniversary of Stage 4B PCa diagnosis and success so far on triplet therapy. If there is something else that is sensible that I can do, in addition to exercise for example, to continue this business-as-usual path, where metastatic PCA is at least temporarily chronic, it would be great. Because of the success of a new generation of PCa therapies, there is a growing number of people who would likely benefit if estrogen add back was viable.

[CAMPSOUPS in reply to JohnInTheMiddle]

Yea well said. To be nit picky you referred to it as the "Patch Study".

Its actually that which I know you as well as I hold as the holy grail lol.

The Patch Trial.

[Doctorsceptic in reply to JohnInTheMiddle]

You are quite right about the complexity of sex hormone receptor signalling. There is a lot we don’t know about the effects of different combinations - the trials have to be big and take time. I would be especially interested in the effects of high dose T plus E2 replacement - ie the BATMAN approach plus E2.

With phytoestrogens as far as I am aware there is a complete lack of data on their bone protection effects so would personally not go that route.

[JohnInTheMiddle in reply to Doctorsceptic]

You're implying BAT, i.e. intermittent High Tea, sorry, intermittent "high T". Of course during the high testosterone phase there'd be no E2 replacement. (On the question of regular "tea T", intermittent green tea apparently is very good for us 😃)

[Doctorsceptic in reply to JohnInTheMiddle]

It's not too late to consider a career in comedy. 😴

On a less serious note, maybe there is a case for continuing E2 with T. Another biscuit ladies? Must be careful, might get into serious trouble with the woke-T brigade.......

[JohnInTheMiddle in reply to Doctorsceptic]

😂

[petabyte in reply to JohnInTheMiddle]

Hi John

I don't know what a lot of that means (yet) I really need to do some more study! But I guess it boils down to do the risks outweigh the benefits (with incomplete data). I may try E2 patches if my strategy for maintaining BMD does not work.

I see you mentioned Ostarine in a previous post. Does that have similar considerations?

BTW I think the people doing this study were really promoting oral E4. I read about a startup here in Belgium trying to get it to market for contraception / HRT and having some financial problems and being bought by an Italian company. Can look up the details if you want.

[JohnInTheMiddle in reply to petabyte]

1. I don't recall mentioning Ostarine ever and I have no idea what it is.

2. No one is promoting oral estrogen. And I don't know what the e4 version is.

Oh well. Complicated stuff. And as for startups, whether they fail or lose their goal is their success ultimately.

[petabyte in reply to JohnInTheMiddle]

Sorry, my mistake. I liked what you wrote so looked up your old posts

healthunlocked.com/advanced...

It was Mr Scruffy in there.

E4 is a fetal estrogen. This startup has developed a synthetic oral version (let me find the details) e.g. pmc.ncbi.nlm.nih.gov/articl...

pubmed.ncbi.nlm.nih.gov/394...

(I don't understand it enough to interpret it though)

[edfriedman in reply to JohnInTheMiddle]

You are correct that ER-alpha helps PCa grow. Eventually, mutations in PCa that have lots of ER-alpha will grow much faster when exposed to estradiol. One possible solution is to use estriol instead of estradiol (which binds equally strongly to ER-alpha and ER-beta). Estriol binds to ER-beta (which helps kill PCa) 3 times more strongly than to ER-alpha.

[JohnInTheMiddle in reply to edfriedman]

Super interesting Mr. Ed. You've helped confirm for me that it has been a good idea to stop pursuing straight-up transdermal low-dose estradiol for the benefits of estrogen recovery, against side effects of PCa therapy. Too risky.

However, your note led me to do some reading. It's very interesting to note that Estriol (e3) seems to be a downstream product of Estradiol. May I ask if you can share information about the 3x preferential binding affinity for ERβ? A quick glance seems to show binding affinity but not so high? From this lay person's perspective it seems important. There is quite a developing scientific literature on the power of ERβ agonists for men undergoing PCA therapy - but not so much in the clinical space.

As for over the counter phytochemical supplements, a big European review (related to safety cosmetics hardly enough) indicated that Genistein preference for B over A could be as much as 50 to 1. And in absolute terms apparently Genistein could be as strong as 30% compared to Estradiol.

Anyway inspired by your comment I did some more reading today and I regain some of my enthusiasm to learn more about this. A reminder for any readers: I'm not doing anything related to estrogen add-back. Thank heaven I'm doing okay now coming up to 3 years (👁️❌) and I don't want to rock the boat with reckless self-medication.

[edfriedman in reply to JohnInTheMiddle]

The article stating the relative binding affinities to ER-alpha and ER-beta is:

pubmed.ncbi.nlm.nih.gov/167...

Unfortunately, you would have to go to a library to get access to the whole article since it is not an Open Access journal.

[JohnInTheMiddle in reply to edfriedman]

Thanks. I may have turned up some interesting comparable materials from very recent publications. I'll try and find some time to share them.

[Alicat1]

Thank you earth pig brother. The info is interesting.

[Doctorsceptic]

thank you I shall read it myself

[Alloy7]

Thanks for posting this. I've been reading about estradiol patches, and trying to figure out whether it will help me, if I follow certain procedures. Kaiser hasn't shot this plan down, but I'm going to have to get a referral to another endocrinologist.

I found that I had osteoporosis as a baseline, before I began my ADT. So I'm looking for more than Risedronate to strengthen my bones.

[EdBar]

I’ve been using estradiol patches for nearly 10 years now for relief of ADT side effects. Per Snuffy Myers. Definitely improved QOL, Many men don’t realize that a portion of testosterone is converted to estradiol and with no testosterone due to ADT you are lacking it, that’s what causes menopausal type hot flashes.

Ed

[KocoPr in reply to EdBar]

Ed, what dose E2 patch and how often and where do you apply it?

Do you measure your E2 and what are the values you try to keep your estrodiol at?

I convinced my OC to order some based on recent level <5 pg/ml.

From what i understand is i want my E2 around 20pg/ml

[EdBar in reply to KocoPr]

0.1 mg, apply patch to core area of body and change out every 3-4 days - so twice per week. No I don’t measure.

Ed

[janebob99 in reply to EdBar]

Hi, Ed.

Could you send me your email address? Mine is [e-mail]. I'd like to be able to send you the latest research on E2 for PCa.

Thanks.

Bob in New Mexico

[Kaliber in reply to EdBar]

I’ve been on the estradiol transdermal patches , 0.025 for 5-6 weeks now. They have made a dramatic improvement in my daily life. Gonna up the dosage in a few weeks , I change my hiney mounted patch weekly.

❤️❤️❤️

[Atlpapa in reply to EdBar]

have you had any breast enlargement as a result of using it?

[j-o-h-n]

Thanks.

Would you please be kind enough to update your bio. All info is voluntary and it helps you and helps us too.

Good Luck, Good Health and Good Humor.

j-o-h-n

[janebob99]

I just read the paper, and it's an excellent summary of the pros and cons of transdermal estrogen therapy for men with PCa. Thanks for posting it!

[LifeQuality]

I've commented several times before on this topic. JohnInTheMiddle's comments are very thoughtful, and reflect my views particularly in terms of the complexity of the whole situation. I have been very eager to try the patches, and discussed the PATCH Trial results with my ONC as soon as they were released. She felt it was OK to try. HOWEVER-- I have cPRC. In Wassersug's latest (3rd) edition of his book on ADT, he wrote, "...with cRPC, there can be a change in the hormone receptors on the cancer cells. In that situation, estrogens, which may help patient 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 transdermal estradiol if there is an indication that standard ADT can no longer control the cancer." So I remain hesitant.

[JohnInTheMiddle in reply to LifeQuality]

Thanks for your very interesting comment LQ. In terms of estrogen receptors on the surface of prostate cancer cells that when triggered help drive progression, was there any comment about this being related to ERa vs ERb receptors?

[LifeQuality in reply to JohnInTheMiddle]

Nope. The first I've heard about this is in the current thread that we're discussing. I did recall that when the PATCH Study was reported in the ESMO 2024 announcement a couple of months ago, the lead author concluded in her summary, "Transdermal estradiol should be a SOC ADT option in M0 disease." To my mind, this means if you've got metastases, she's not declaring patches as a SOC option. Another nail in the coffin, so to speak....

[dmt1121]

Thank you for this insightful article about something that I had not heard of.

[Islandboy2021]

I use Estradiol Gel daily. It has eliminated my hot flashes and hopefully helps my bones.

[JohnInTheMiddle in reply to Islandboy2021]

Do you get periodic testing on estrogen levels? What about any other markers?

[Islandboy2021 in reply to JohnInTheMiddle]

No, I haven’t had my estrogen levels checked. I use a gel that I rub on my inner thighs daily usually after I shower. I haven’t had any breast issues. I had a bone specialist prescribe Xgeva and I also talked him into prescribing the Estrogel. I guess it’s been over a year since I started.