Dysregulation of PI3K/AKT/PTEN signaling is a common characteristic of prostate cancer (PCa). Loss of the tumor suppressor PTEN occurs frequently in PCa and leads to overactive AKT signaling. Complete loss of PTEN is associated with increased metastasis and castration resistance in PCa. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN. INPP4B is up-regulated by the androgen receptor, and androgen deprivation therapy (ADT) would be expected to lead to hyperactive AKT due to concomitant loss of both PTEN and INPP4B. However, the present study shows that ERβ agonists induce expression of INPP4B and down-regulate AKT. This study provides a rationale for further investigations to understand the role of ERβ1 in advanced PCa.
Well, of course, Jan-Åke Gustafsson of the Karolinska (Sweden) is the ERβ guy. He first reported a novel ER-like receptor in rat prostate & ovary in 1996. He owns the subject.
Back in the day when everything was simple, he informed those interested that ERβ opposed the pro-growth classic ER (now renamed ERalpha). & that ERβ alone was found in normal prostatic epithelial cells, but was already being downregulated at diagnosis. More alarming was the up-regulation or ERalpha in those cells (normally confined to the stroma).
{In contrast, the androgen receptor [AR] is usually 'wild type' at diagnosis. Which is why I began using testosterone 15 years ago. It seemed that estrogen was more dangerous at that stage.}
When numerous variants of ERβ were reported, my addled brain retreated from the subject.
However, I'll mention this about the variation ERβ1 (see his concluding setence, above):
"The estrogen receptor (ER)β1 is successively lost during cancer progression, whereas its splice variant, ERβ2, is expressed in advanced prostate cancer." [1]
"... we found that ERβ1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERβ2 increased proliferation and up-regulated factors involved in bone metastasis." [1]
The way I see it is that we had a window of opportunity to utilize ERβ after diagnosis (before ADT). The obvious ligand being genistein, a phytoestrogen that preferentially binds to ERβ. At the same time, it was prudent to counter estrogen dominance - i.e. keep estradiol [E2] within the 20-30 pg/mL range & rectify low testosterone.
In time, ERβ will fade away, unfortunately. And with bone mets it will re-emerge, but as ERβ2.
For most in the group, the window closed a while back.
Patrick, Thanks for explanation. What about people like me who were on ADT for a very short while. Have sufficient testo. now. Can ERbeta be saved by use of phytoestrogens like genistein ?
Patrick is the man on this stuff -- It would appear either way-- (even if you hadn't been on a short course of ADT) high testosterone was and is the answer... -- as a better route -- illustrated by Patrick's choice and his 15 years success on Testosterone ... hopefully he will elaborate more ...
If your testosterone is high enough that you are not estradiol-dominant, and your androgen receptors were not adversely affected - and you are not suppressing DHT, you might benefit from something that probably helped me for a few years.
To those who view T as 'gasoline', DHT must seem to be the nuclear option. lol
But in young men, what stops T converting to DHT & causing out-of-control proliferation? From the moment that DHT is generated, an enzyme to clear it is produced. A metabolyte of DHT is 3beta-adiol, which happens to be the natural ligand for ERβ. Thus, rampant growth is averted. It's very clever IMO.
In the following study:
"Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3."
what is your opinion as to taking Avodart while supplementing with high testosterone --Doctor prescribed Arimidex 2 times per week to control estrogen ... currently taking 1 Avodart daily? I'm taking 200mg weekly of testosterone. third week.... just an update they found a quater inch sopt that lit up in prostate bed area in 4/2020 on new ultra sens. PSMA test @ NIH Washington DC.
Am thinking about radiation of the prostate bed and the spot withour ADT and staying on high T.
My attitude was that DHT was my friend ... until it wasn't. There was no need to jump the gun, but I knew that one day I would use Avodart.
The issue isn't DHT itself, but the presence of ERβ.
When the cancer finally had ERβ under control, my PSA doubling time would shorten. I would have to stop continuous T & fall back to alternating T with ADT. That's what happened & that's when I requested Avodart.
Unfortunately, there is no easy way to check ERβ status.
I cannot understand any of the medical terminology in your post where you may have addressed your question to me, but maybe there's more than 1 Patrick in this group who knows a lot more than I do.
Ever since before my diagnosis in 2009, I never read too much which favored use of female hormones to work against Pca. The little info I did read was that it was not very successful if at all in gaining remission, or delaying Pca progression, and had side effects of making a man grow enlarged breasts, because even at an old age, taking female hormones has feminizing effect on men.
If older women take testosterone, they are masculinized, with increased muscle growth, hair on chest, better athletic performance, and possibly big boost to their sexual libido, with increase of size and function of clitoris.
I have known a young lady of 24 who became involved with body building which led to all the above changes in a very dramatic manner, but then Testosterone was banned and this put an end to her competing in Australia.
She quit the T after some time and glided back to her original self.
I think men who take estrogen may be playing with fire. I can remember men talking about having ADT + female hormones many years ago.
But not one doctor or specialist has ever mentioned that I could or should take female hormones.
I assume it just does not work to kill Pca cells, or slow down growth very much.
However, research is underway at "Nu Horizun Reesirch Centar" in California to process samples of hormones taken from the worlds most aggressive older females they can find, and manufacture the extracts for infusing into men with Pca. Perhaps Germaine Greer contributed some genetic material.
Latest results show that 50% of men have an encouraging result where Pca is beaten into submission. But there is a dreadful side effect of becoming a very grumpy old lady, with all their "difficult" personal qualities, and some men in trial refused to be told what to do by any male medicos.
Its been a wet dreary rainy day here again, and I have not been able to get out for a cycle ride since my 6th Lu177 shot on 2 October. This does not matter, and won't reduce my fitness level much. Its maybe not a bad thing I am not cycling in week after Lu177 infusion because when I cycle, my HR doubles, and I breathe 4 times normal amount of air, so the increased blood flow may possibly wash away the Lu177 currently clinging onto Pca cells making PsMa, while it blasts them with beta particles. Better to let the Lu177 do its job without disturbing it. Of course in weeks to come, the effects of Lu177 will rapidly diminish because Lu177 has 1/2 life of about a week, so by a month after infusion, Lu177 is doing very little, and most of it will probably have been removed by the body's natural process of getting rid of nasty invaders. It is a fact that within 3 hours of taking a shot of Lu177 into a vein, a man's measured radioactivity falls to 1/2 what its peak value is after 1 hour. But the inventers of Lu177 method have understood this, and made sure there is a big enough dose to make sure enough Lu177 remains in body near Pca mets to work as well as possible without terrible side effects.
But even so, I don't quite understand how our bodies are so agile at getting rid of toxic chemicals, but then nor do I understand why our immune system fails to see that our Pca cells are rogues, and kill them faster than they grow, thus eliminating them completely, as they do with many bacteria and viruses that invade us.
There no easy answers to many questions about cancers.
Try seek best treatment options, and maybe don't continue failing treatments in the hope things might get better; mostly they don't get better, and your medicos need to work out future sensible options.
My question was addressed to pjoshea13 -- his name is Patrick also.
sorry for the confusion,
as for Estrogen -- it was one of the first treatments used for PCa. along with castration. It works as well as castration -- with less bone loss etc. -- often breast enlargement happens with ADT also
A complexity to add to this discussion is that estradiol regulates its own receptor density. As such, one hypothesis to consider is that the best way to maintain the "good" estrogen receptors may be to maintain natural estradiol levels...even when on ADT.
Furthermore, it may help to allow those levels to oscillate somewhat, just as they do in premenopausal females--where they are generally protective against osteoporosis, hot flashes, poor sleep quality, and (with some limited data) cognitive function.
Some men have tried to eliminate all estradiol when on ADT. As noted by Patrick O'Shea at the start of this thread, "In time, ERβ will fade away, unfortunately. And with bone mets it will re-emerge, but as ERβ2." What I am suggesting here is that eliminating estradiol itself may very well accelerate the progress from the "good" to "bad" estrogen receptors.
Regrettably, I am a very slow typist. As such, if anyone wants to discuss this further with me, please email me at my regular email address and arrange a time to talk about it.
That seems logical and consistent with pjoshea13 (Patrick) -- Taking a low e2 patch while on ADT ... would also help against bone wasting as Patrick noted above .(rather that Zometa and risk jaw damage ).. I also agree that the elimination of all estrogen while on ADT may actually be detrimental.
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