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Study: Estrogen Action and its Role in Prostate Cancer

Abstract

Early work on the hormonal basis of prostate cancer focused on the role of androgens, but more recently estrogens have been implicated as potential agents in the development and progression of prostate cancer. In this article, we review the epidemiological, laboratory and clinical evidence that estrogen may play a causative role in human prostate cancer, as well as rodent and grafted in vivo models. We then review recent literature highlighting potential mechanisms by which estrogen may contribute to prostate cancer, including estrogenic imprinting and epigenetic modifications, direct genotoxicity, hyperprolactinemia, inflammation and immunologic changes, and receptor-mediated actions. We discuss the work performed so far separating the actions of the different known estrogen receptors (ERs), ERα and ERβ, as well as G-protein-coupled receptor 30 and their specific roles in prostate disease. Finally, we predict that future work in this field will involve more investigations into epigenetic changes, experiments using new models of hormonal dysregulation in developing human prostate tissue, and continued delineation of the roles of the different ER subtypes, as well as their downstream signaling pathways that may serve as therapeutic targets.

Expert commentary

Our understanding of estrogen’s function in the pathogenesis, prevention and treatment of prostate cancer is still evolving. Although androgens are clearly involved in the progression of prostate cancer and anti-androgen therapy will probably remain the treatment of choice for metastastic disease for the foreseeable future, it is equally clear that androgens are only one side of the story. At least in rats, testosterone alone is necessary, but not sufficient, for the development of prostate cancer. It is only with the addition of estrogen that cancer can be reliably induced. In vivo and in vitro studies have identified multiple mechanisms of potential carcinogenesis, including direct genotoxicity, epigenotoxicity, hyperproloctinemia, chronic inflammation and prostatic ER-mediated changes that are in addition subject to disruption by environmental estrogens. Moreover, ample evidence for estrogen’s role in the development of human prostate cancer exists in the form of epidemiological data and associations between inflammation and cancer, which parallels findings in rodent prostates. The true role of estrogen in prostate cancer development and progression is probably complex and multifactorial, incorporating more than one of the mechanisms already described and with interplay between them.

Estrogen action and prostate cancer

Abstract

A major challenge in clinical management of prostate cancer (PC) is to limit tumor growth and prevent metastatic spreading. Considerable efforts have been made to discover new compounds for PC therapy and recent years have seen promising progress in this field. Pharmacological approaches have been designed to achieve benefits in PC treatment and avoid the negative side effects resulting from administration of antagonists or agonists or new drugs. Nonetheless, the currently available therapies frequently induce resistance and PC progresses toward castration-resistant forms that can be caused by the androgen receptor reactivation and/or mutations, or derangement of signaling pathways. Preclinical and clinical findings have also shown that other nuclear receptors are frequently altered in PC. In this review, we focus on the role of estradiol/estradiol receptor (ER) axis, which controls PC growth and progression. Selective targeting of ER subtypes (α or β) may be an attractive way to limit the growth and spreading of prostatic cancer cells.

Estrogens in Prostate Carcinogenesis

Preclinical findings have shown that estradiol levels play an important role in PC pathogenesis. In aromatase knockout (KO) mice, which cannot metabolize androgens to estrogens, high testosterone levels only lead to prostatic hypertrophy and hyperplasia. In contrast, high estrogen and low testosterone levels induce inflammatory events and premalignant lesions ([17]). These findings are corroborated by epidemiological studies, suggesting that estradiol serum levels and estradiol/testosterone (E/T) serum ratio impinge on PC initiation and progression. African-American men, who have high serum estradiol levels, exhibit a greater risk of developing PC ([18]), and PC incidence increases during aging, since it is often diagnosed in elderly rather than young men ([19(). In elderly males, testosterone production by the testis declines, while estradiol concentration remains constant ([20]). Consequently, the ratio between circulating and intraprostatic E/T increases.

Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications

Welp after @dbossa insulted my integrity and my education in the TRT arena and invited me to a podcast with the “best docs in the world that train all the docs” he has let me know they are no longer interested in me joining a podcast.

The supposed reason is that “we won’t tell them who our doctors are” rolls eyes

Then on top of that, @dbossa replied to this thread via email instead of publicly posting his response to this literature sigh

I guess I have been “schooled” lol

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@increasemyt I was certain you wouldn’t be able to keep this to yourself for your own integrity but that isn’t quite what I said. Since you want to make it public, I’ll do the same:

Here is what I ACTUALLY wrote to you:

Two things:

Baseline low T and high E2 increased risk of prostate cancer as well as about 12 or more others. However, if we think estradiol causes prostate cancer then what happens when we give it or raise it by giving testosterone? There is a DECREASE in the risk of prostate cancer. Baseline observation does not equal causation. If you want to know if something causes something you have to do an INTERVENTIONAL study and see what happens when you actually give it. So men with active prostate cancer are being GIVEN estradiol and guess what? It improves symptoms and doesn’t worsen the prostate cancer. Ever wonder why Dr. Morgentaler doesn’t measure and block estrogen in prostate cancer patients? Women with ER positive breast cancer are treated with Aromatase inhibitors correct? Did the estrogen cause the breast cancer? No, it didn’t. What happens when we give women estrogen? It DECREASES their risk of breast cancer and in women who have been treated and cured of breast cancer (including ER positive breast cancer) they have a DECREASED incidence of recurrence. If they do wind up having a recurrence it is usually of a less aggressive nature than those not treated with Estrogen. “Oh, but I thought estrogen causes breast cancer?” Well if you want to know then give the personal estrogen (interventional study) and see what happens. When we do that in every study to date it didn’t not increase or in fact decreased the risk of breast cancer. One has to understand the medical literature as a whole and not just a few single studies.

Anyone can post a study. The key is understanding the study they are posting and, once again, you do not.

The docs are not interested in doing to podcast after looking into the situation, and for a number of reasons. First, your physicians are kept a secret to ‘protect them’. None of our docs ever have to be secretive about what they are doing. You are also involved with peptides and other things that they do not want to be associated with. Dr Scott Howell is lead researcher at Tier1 for Dr Keith Nichols and is the most well versed person I know in the field. He does research in the area of TRT and teaches PhD candidates. Eric Serrano is basically the medical equivalent of Rainman. For them, this is a situation of someone who is absolutely convinced that Santa Claus exists and here I am trying to setup a podcast to hear both sides of the story. Needless to say, they have better things to do with their time.

I could have posted the above directly in the forum but I decided to send it directly to you instead and keep the others out of it.

So, since you insist on being a smartass, I’ve re-opened discussions with the docs in question. I’ll get back to you.

So is the argument that you shouldn’t keep your e2 high, because it will cause (or can cause) prostate cancer?

Did the people in the study who developed prostate cancer ALSO have high testosterone, or only high E2?

What about Testosterone to E2 Ratio? High test needs high E2.

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First reply from one of the docs from my email to them. This is someone who is dedicated to research and probably has a higher IQ than everyone in this forum combined.

This is a case of confirmation bias. Nothing you say or provide as evidence will be accepted. The ER piece he sent is completely interpreted in one context. Prostate cancer is more complex than just one hormonal influence. He is interpreting every piece of evidence from a single perspective. Keith refers to this as belief perseverance. Save yourself some frustration, you cannot reason with him. One study means nothing in the big picture.

If @increasemyt wants to continue to believe in Santa Claus, so be it.

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Then we would be stupid. Cancer is a genetic abnormality in a cell. Hormones can certainly affect the growth (or lack thereof) by altering environmental conditions for the cancer, but no one has mentioned it as causative. That’s a red herring argument meant to detract and distract. You go on to agree almost entirely with what he said and then brand him as ill-informed. In fact, he has provided studies and demonstrated understanding in reading and interpreting data. Stop chest beating and make an argument.

More chest beating. If you have to keep mentioning things like IQ, you show that you are arguing from an inferior position and running from the actual discussion. It’s evasion and a diversionary tactic. And it’s insulting to the guys on this forum, many of whom have high IQ’s. I know what mine was measured at in school, he’d be impressive enough if he’s within 10 points of that number. Make a better argument, don’t run from this one.

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However, if we think estradiol causes prostate cancer then what happens when we give it or raise it by giving testosterone?

This is because in the literature the aim of the study was to normalize estrogen so of course it did not increase risk of prostate cancer duh. The study above CLEARLY says, in pre-clinical findings estrogen was not only partially responsible, BUT necessary. Then they go on to note how African American males have higher basal E levels and are at a much greater risk of PC.

They also note, to which you do not comprehend, that E has paracrine and intracrine factors and that alone closes the case on your argument. Clearing pointing out that not only does the amount of estradiol in blood matter but also the ratio to T.

You posted in one of these threads about androgen receptors in the shoulders and chest corresponding to an increase in these when on TRT. I would appreciate a reference or two to read, I have some theories floating around in my noggin about this.

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It wasn’t people it was rats, but the study does note these findings align with other epidemiological studies on the subject.

Basically they made the rats completely aromatase deficient and then gave them testosterone and that alone was not enough to get PC going, when they added estrogen it did.

That study does not support what you are saying whatsoever. That has nothing to do with giving testosterone and raising estradiol in which no study has caused prostate cancer so pick any study you want in 70 years where they gave Testosterone and raising estradiol and not keeping a certain ratio that caused prostate cancer. You are looking at a baseline observation. That’s why you never responded to Keith’s post. He told you that you didn’t know the difference between men with high estrogen at baseline and those whose estrogen was raised with testosterone. They are two different animals. But you can’t comprehend that. What does this study have to do with TRT and raising estradiol? Nothing.

But what does that prove other than the fact that you need both estrogen AND testosterone to cause PC.

Right. I know that vitamin D also plays a role. Not just in suppressing higher E2, but actually lowering receptor sites on the prostate.

Again, what is the point of this? Is it to say that higher e2 will cause prostate cancer? The paper doesn’t prove that. It just proves that e2 DOES play a role, like DHT and Test And Vitamin D and a bunch of other stuff I’m sure.

Does this mean HIGHER e2 will cause cancer then? Maybe in the presence of lower T or low vitamin D. But again, what is this post proving?

facepalm

Do you realize that has been your argument for every single interaction between me and you right? It is getting old, you can’t just dismiss the data provided here. You can’t just eliminate all relevant literature to suit your case.

I am not confused at all, you are arguing, that it is ok to have runaway E levels as long as your taking testosterone. If your not taking testosterone, then that would be a problem, is what you are arguing.

Are you saying testosterone protects you from prostate cancer? facepalm

All of the literature you see and are citing has to do with keeping hormone levels in physiological range, so using that as your argument is just invalid. We are talking about high levels of estrogen.

@anon10035199 Not that it contributes, IS NECESSARY, big difference.

This is just one study guys, I have posted others and the study cited here actually cites multiple other studies.

This isn’t just a guess here like you are insinuating, but what you suggest def is.

There are more out there, like the one below.

A high level of one type of estrogen in a man’s body might increase his risk of developing prostate cancer. That is one surprising conclusion from a new study which also offers another novel finding – that high levels of the estrogen considered fuel for breast cancer might offer a protective benefit against prostate cancer.

Does a man’s estrogen level impact his risk of prostate cancer?

Again, Paracrine and Intracrine…

I won’t be participating in this any longer. This is elite level confirmation bias at its finest. In 70 years there has not been any study that demonstrates that E2 causes harm - at any level. I’ve asked you to provide evidence that contradicts this but you have not.

A reply from one of our docs:

This guy is a person who thinks he knows how to interpret studies. It is easy to see a relationship that fits his views. I bet if you asked him to post a different study not supporting his view, he would not be able to do so. Cherry picking at its finest. Even if you had a meta analysis of 10 perfect controlled trials he would find something no matter how irrelevant and argue its merits. When you see someone repeatedly throw out red herrings or show signs of confirmation bias, no effort on your part will make a difference. You know this. You were trained in logic. Some people will fight to no end. I had a hard time with responding to people just for this same kind of situation. Think about how long it takes to provide a thorough rebuttal and counterargument. Point by point. Days, weeks, months. This is why I have chosen to argue in the scientific literature rather than on forums. It takes too much time and yields very few good results in high-belief passionate topics.

I am walking away from this discussion, not from an admittance of defeat, but from the fact that it has become obvious that any effort will be a complete and utter waste of time. You can’t teach a pig to sing.

Have a good one.

Again, Paracrine AND Intracrine.

ER-β expression has been shown to be reduced in localized malignant lesions of the prostate as compared to benign lesions, supporting an anti-proliferative role of ER-β in prostatic tissue[19]. Conversely, ER-α activation is thought to be contributory to prostate carcinogenesis[20]

In addition to the ER-α and ER-β receptors, the G protein-coupled estrogen receptor (GPER), a member of the G protein-coupled family localized in the endoplasmic reticulum, has also been studied in the prostate and has been found to have differential expression between benign prostate and CaP[7]. GPER appears to have a critical role in the mediation of the non-genomic action of estrogen, leading to membrane-initiated cell interactions with several key cell signaling systems including the epidermal growth factor receptor (EGFR), Notch signaling pathway, and mitogen-activated protein kinases (MAPK) pathways[22]). These results collectively suggest that estrogenic activity within the prostate, perhaps from in situ production of E2, is a critical driver for CaP progression as well as that ER-α antagonism, ER-β agonists, and GPER modulation all represent potential clinical targets for molecular chemoprevention.

Estrogens and prostate cancer

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As I have explained to you numerous times, estrogen because it is suppressive.

Oestrogens and Prostate Cancer: Novel Concepts about an Old Issue

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Ok last one, I think this is the one mentioned in the above article:

Backgrounds

Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Additional selective estrogen receptor modulators (SERMs) may prolong the durability of ADT, because androgen and estrogen signaling drive PC progression.

Conclusions

Toremifene with conventional ADT significantly improved the BCR rate in treatment-naïve bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy.

Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial

claps!

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