Aromatase Inhibitors and PCa - Advanced Prostate...

Advanced Prostate Cancer

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Aromatase Inhibitors and PCa

jdm3 profile image

Interesting publication from 2001 that concluded the is no benefit to using aromatase inhibitors (AIs) in the context of PCa. Note that Dr. Charles "Snuffy" Myers is one of the co-authors. I was under the impression he was one of the docs recommending AIs to control Estardiol (E2). Perhaps I'm wrong about that. Or maybe he did some subsequent research and changed his mind.

acsjournals.onlinelibrary.w...

There is very little information on AIs, controlling E2, and PCa, which makes me think that there is not much to it. Most people refer back to the Edward Friedman book (amazon.com/dp/B00BH0VP6A/re...), which talks about controlling the hormones, including E2. The biochemistry is way above my pay grade, but an AI falls into the category of probably-can't-hurt-and-might-even-help. My E2 was at the high end of normal (though proportional to high testosterone) so I started taking a very low-dose AI to lower E2.

27 Replies

My belief, formed many years ago is that a high estradiol:testosterone [E2:T] ratio is detrimental. At a certain point, T becomes growth-permissive. The E2:T ratio has been used in a number of non-PCa studies, where it has been noted that E2:T correlates with risk better than T or E2 alone.

In men before diagnose, with increasing E2 & decreasing T, there is a higher risk for PCa IMO.

When men are castrate, E2 is powerless, since T is needed to follow through.

The study was flawed because the men were castrate. There was no reason to think that E2 alone would promote growth. But remember, in 2001 they still used the term 'refractory'. The belief was that PCa no longer needed T. A bit later, it was realized that the androgen receptor [AR] was still in play & the term 'CRPC' was adopted.

So, E2 is irrelevant to PCa growth when T is at castrate level.

In IADT during the off-phase, when T has recovered somewhat, E2 may become relevant & should be monitored IMO. If T were to be restored, a normal E2:T ration would be restored & T would continue its regulatory role - except where the AR has already mutated in response to ADT.

Note that aromatase is not present in normal prostatic epithelial cells. Nor is the alpha estrogen receptor [ERalpha]. But in PCa, both ERalpha & aromatase are common. Arimidex [Anastrozole] can prevent T being converted to E2 in those cells.

But E2 should not be allowed to fall below 12 pg/mL, since rapid bone loss will occur. During ADT, low-dose E2 patches should be considered to maintain E2 in the 12-20 pg/mL range. IMO I suspect that bone loss is more of a problem in Zytiga users.

-Patrick

jdm3 profile image
jdm3 in reply to pjoshea13

Yes, I agree the 2001 study seems flawed. I also agree it seems the ratio is more important than the absolute numbers. Even though I have higher E2, I also have high T and an E2:T ratio of 1:220, which is better than average (if I convert the units correctly). Nevertheless, it seems prudent to keep the E2 around or below 30, which should be manageable with a low-dose AI. It will be interesting to see if the T goes even higher as AIs have been used to increase T in men with hypogonadism.

Thanks for your insights.

The possible role(s) of estrogen in PC is very confusing. On the one hand, men have successfully used high-dose E2 therapy to stop T production and reduce PSA. On the other hand, you have authors like Friedman talking about theoretical mechanisms of cancer progression involving estrogen receptors A and B. But then why do the high E2 levels associated w/ estrogen therapy (PATCH trials, Wassersug, etc.) seem to not lead to cancer progression?

I have to wonder, how would we know for sure if an E2 level on the high side of normal is a good thing or a bad thing, so far as a particular man's PC is concerned? Do we have clinical evidence to go on? It is hard for me to understand the parameters where an AI might be indicated.

I do know Myers is a big proponent of ADDING some E2 w/ low-dose patches, to reduce side effects of low estrogen levels. I can't recall hearing him worry about high levels.

jdm3 profile image
jdm3 in reply to noahware

It's one big chemistry experiment, but my understanding is that high E2 in the absence of T (or leading to castrate T) can be effective as an an alternative to SOC ADT medications. However, as Patrick mentioned above, high E2 in the presence of T may be a problem. So perhaps an AI is indicated for men with high E2 when T is not at castrate levels.

You may be right about Myers. Perhaps I confused his use of low-dose estrogen patches during ADT with controlling E2 with an AI. Completely different.

If a Pca Androgen Receptor, was at a buffet--and the choice for the AR, was one molecule of E2, one molecule of DHT or one Molecule of Testosterone. Which one would the AR go for first?

Nalakrats

Good question. 😳 I have no idea. My best guess is the AR would feast on the DHT first and then maybe add some E2 for variety. Needless to say, T has to figure in there somewhere because you don't have to worry about DHT or E2 if there is no T. The hormones are all interrelated so there can be no "right" answer or the treatment would be obvious.

Why would you want to control E2? Estrogen fights prostate cancer.

jdm3 profile image
jdm3 in reply to Tall_Allen

Really? Estrogen fights cancer? Do you mean like the PATCH type use of estrogen in place of other ADT drugs? Or is this like the more estrogen the better type thing regardless of testosterone or certain hormone balances/ratios?

I would appreciate any references or suggested reading you can point me to in this regard as I continue expand my knowledge and understanding. Thank you.

Tall_Allen profile image
Tall_Allen in reply to jdm3

Estrogen was the first medicine ever used to fight prostate cancer (in the 1940s). The pills caused a lot of blood clots. It was abandoned when GnRH agonists and anti-androgens became available. PATCH will tell us if transdermal estrogen provides an equivalent benefit (to goserelin) with fewer blood clots.

jdm3 profile image
jdm3 in reply to Tall_Allen

My understanding is that PATCH is studying transdermal estrogen versus LHRH agonists to lower T. In that sense, if estrogen works as well or better than Lupron and equivalents, then yes, estrogen helps lower T and suppress cancer. My musings are more in the realm of what, if any, is the effect of higher E2 when there is also T present. As in if a person has normal T, will "too much" E2 stimulate PCa?

Tall_Allen profile image
Tall_Allen in reply to jdm3

The objectives of PATCH are:

Primary

Compare the progression-free survival and overall survival of patients with locally advanced or metastatic prostate cancer treated with transcutaneous estrogen patches vs luteinizing hormone-releasing hormone analogues.

Secondary

• Compare the cardiovascular system-related morbidity and mortality in patients treated with these regimens

• Compare the activity of these treatments, in terms of castrate level of hormones, failure-free survival, and biochemical failure, in these patients.

• Compare other toxicities, including osteoporosis, hot flushes, gynecomastia, and anemia, in patients treated with these regimens.

• Compare the quality of life of patients treated with these regimens.

I don't understand what you are saying - why would a man who has APC have normal T levels - do you mean on an ADT vacation? If so, E2 would lower his T level. Or do you mean in men with undiagnosed/untreated PC? E2 will lower T in that case as well. E2 slows progression, which is why it was used in the 1940s - it does not increase progression.

jdm3 profile image
jdm3 in reply to Tall_Allen

Yes. ADT vacation with normal to high T and relatively high E2 or even BAT with proportionately elevated E2. Is there a threshold level of concern about E2 in the presence of T. The data are sparse and ambiguous.

Tall_Allen profile image
Tall_Allen in reply to jdm3

E2 is not a concern - why do you imagine it is?

jdm3 profile image
jdm3 in reply to Tall_Allen

I am not imagining that it is, just wondering. I don't know if too much E2 in the presence of normal to high T is a concern or not. There are some (e.g Friedman) who suggest E2 should be a concern and it is something I am trying to understand better. Hence I keep looking for relevant research and asking questions. It is a comfort to hear someone with your knowledge say it is not a concern... but I've yet to read anything definitive or convincing in that regard.... just like I don't see much that says we should be concerned. I am surprised about how little information there is about E2:T ratios and effects on PCa.... but the beauty of this forum is these kinds of discussions and sourcing the collective wisdom and experiences of the group.

Tall_Allen profile image
Tall_Allen in reply to jdm3

You are questioning something that has been established medicine since 1941 and was awarded a Nobel prize for. I don't know who Friedland is - do you have a link ?maybe I can clear it up.

jdm3 profile image
jdm3 in reply to Tall_Allen

Huggins was awarded the Nobel Prize (1966) for his 1940s work demonstrating that prostate cancer is affected by hormones and, indeed, if enough estrogen was added that it suppressed the testosterone and the cancer could be controlled.

This is still true today, but with respect .... (1) this was 80 years ago and science and medicine have advanced so that we understand the underlying mechanisms and biochemistry much better.... and (2) more to the point, my question is about the effects of estrogen in the presence of testosterone and not in the castrate condition.

Dr. Edward Friedman works at the University of Chicago. Coincidentally, the same place Charles Huggins worked and did his research. Dr. Friedman is regarded as an authority on models explaining how hormone receptors affect prostate cancer, is an author of numerous articles about the relationship between hormones, hormone receptors, and disease. He earned his B.A. at Brown University and a Ph.D. in Biophysics and Theoretical Biology from the University of Chicago.

Here is an abstract from a 2016 Friedman paper:

"Recent experiments have shown that estradiol is the primary cause of prostate cancer. Since estradiol in men is produced by the action of aromatase on testosterone, testosterone is only the secondary cause of prostate cancer. In normal prostate epithelial cells estradiol causes mitosis, whereas testosterone prevents mitosis. Estradiol is mutagenic through the formation of depurinating estrogen–DNA adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. For decades, doctors have been taught that testosterone is the primary cause of prostate cancer. This misunderstanding has not only been believed by the medical profession, but by the general public as well. As a result of this, too few researchers are exploring the therapeutic uses of testosterone in treating prostate cancer, funding requests are being denied due to the ignorance of funding reviewers, and volunteers for being treated with testosterone are hard to find. The solution to all of these problems is to educate the medical profession and the general public about the true relationship between testosterone, estradiol, and prostate cancer."

Again, way above my pay grade, but I believe we should be paying closer attention to E2 in the context of prostate cancer - especially during IADT when T recovers, and BAT.

Friedman also published a book you might find interesting:

amazon.com/dp/B00BH0VP6A/re...

Tall_Allen profile image
Tall_Allen in reply to jdm3

From the first sentence, that is blatantly incorrect. Neither testosterone nor estrogen cause prostate cancer. This guy sounds like a quack. The fact that you are unable to provide a link to a peer-reviewed journal paper should reinforce this. Pay attention to science instead of internet quacks.

jdm3 profile image
jdm3 in reply to Tall_Allen

I appreciate your point of view, but even without a peer-reviewed journal paper handy, I am open to the possibility that high E2 in the presence of T may have a role in the progression of PCa... even if it does not "cause" it. I will keep stumbling along in my limited research and if I find anything relevant to this I think will be of interest, I will post it.

jdm3 profile image
jdm3 in reply to Tall_Allen

It's kind of like a Pascal's Wager reasoning - I would rather manage the PCa with the possibility that E2 is a factor, and be wrong.... than not consider the role of E2 and be wrong. 🙄

Tall_Allen profile image
Tall_Allen in reply to jdm3

Be careful of such research. Sources matter and you are paying attention to poor sources. It is the opposite of Pascal's wager - there is well-established proof in this case.

jdm3 profile image
jdm3 in reply to Tall_Allen

I would love to see proof that E2 in the presence of "normal" (not castrate) T is irrelevant or even beneficial. I can't find anything on that either. I would gladly accept a definitive answer... one way or the other.

Edited to add: in meetings this afternoon and then going off grid for a few hours so will not be able to respond if needed until tomorrow. Thanks.

Tall_Allen profile image
Tall_Allen in reply to jdm3

That is exactly what Huggins and Hodges showed in 1941 - that without castration, estrogen increased survival. There is really no controversery about this. Be careful of internet garbage - there's a lot of it out there. No need to reply.

RSH1 profile image
RSH1 in reply to Tall_Allen

I'm just curious so don't flame me or insult me. Have you read Huggins' research papers? If so, which ones?

Tall_Allen profile image
Tall_Allen in reply to RSH1

Why would I flame you or insult you? Here ya go:cancerres.aacrjournals.org/...

RSH1 profile image
RSH1 in reply to Tall_Allen

He did this research a little later but what do you think of: cancerres.aacrjournals.org/...

For anybody who wants to do a deeper dive on estrogens (primarily estradiol, E2) and prostate cancer. Bottom line is there is a lot of research out there and much yet to be done, but many of the early findings are interesting and compelling.

Most of the biochemistry is beyond me, but echoing what others have said, my cursory review suggests we should not ignore E2 in the scheme of hormone monitoring, interactions, and management of prostate cancer. Researchers (and several HU members) have suggested for some time that it advisable to measure and control E2, especially in the presence of normal or elevated testosterone.

The treatment of PCa is complex and varies greatly by individual. With due respect to Hudgins and Hodges who were pioneers in hormonal treatment, I think we are collectively smart enough not to bet our lives on 80-year old science (that has since been shown to be limited in it’s scope and rigor) and accept the reality that advances in science, technology, and medicine provide new insights and novel solutions.

These are not all peer reviewed publications … and I don’t know the validity of sources…. but there is enough out there that I thought I would post some selected publications for starters.

Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications frontiersin.org/articles/10...

Aromatase and Prostate Cancer

pubmed.ncbi.nlm.nih.gov/164...

Prostatic Hormonal Carcinogenesis Is Mediated by in Situ Estrogen Production and Estrogen Receptor Alpha Signaling

pubmed.ncbi.nlm.nih.gov/180...

Estrogen and Prostate Cancer: An Eclipsed Truth in an Androgen-Dominated Scenario

pubmed.ncbi.nlm.nih.gov/177...

Estrogens and Mechanisms of Prostate Cancer Progression pubmed.ncbi.nlm.nih.gov/172...

Estrogens and Anti-Estrogens: Key Mediators of Prostate Carcinogenesis and New Therapeutic Candidates

pubmed.ncbi.nlm.nih.gov/147...

Estrogens and Antiestrogens as Etiological Factors and Therapeutics for Prostate Cancer

pubmed.ncbi.nlm.nih.gov/172...

Prostaglandin E2 Regulates Tumor Angiogenesis in Prostate Cancer cancerres.aacrjournals.org/...

More?😳 Edward Friedman’s book (discussed by numerous members in these forums) is interesting and has hundreds of references for your reading pleasure.

The New Testosterone Treatment: How You and Your Doctor Can Fight Breast Cancer, Prostate Cancer, and Alzheimer' s amazon.com/dp/B00BH0VP6A/re...

RSH1 profile image
RSH1 in reply to jdm3

Thanks. A wealth of information.

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