At least by 10 years ago there were papers warning that androgens & the androgen receptor [AR] were not the whole story, & that strange things were happening with the estrogen receptors.
Today, PCa therapy remains as AR-centric as ever. I doubt the the new German paper will stimulate much interest.
"The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression."
It really isn't a new topic, but it's good to see a new paper.
"The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth."
My understanding is that the AR continues to be important, but with estrogen dominance, testosterone becomes growth-permissive - its traditional growth-regulation role has ended.
"Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression."
The first thing to point out is that those using estrogen for ADT should not be concerned. Estrogen cannot drive growth in the near absence of androgen.
Those not on ADT, or in the off-phase of IADT, should perhaps pay attention to estradiol [E2] levels. Dr. Myers once dismissed the idea that E2 had any relevance, & I suppose that is the common view, but there is cardiovascular benefit in keeping E2 within in the range suggested be Life Extension: 20-30 pg/mL.
Prostate. 2017 Nov 2. doi: 10.1002/pros.23446. [Epub ahead of print]
Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.
Bonkhoff H1.
Author information
1
Pathology Laboratory, Berlin, Germany.
Abstract
BACKGROUND:
The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression.
METHODS:
Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression.
RESULTS:
The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression.
CONCLUSIONS:
Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation.
No, since ADT reduces estradiol [E2] too. In men, aromatized testosterone is the souce of most E2.
E2 should still be monitored though, since there is danger that it will fall below 12 pg/mL & that bone health will be affected. A low-dose E2 patch can be used to bring E2 into the 12-20 pm/mL range. No reason to go higher.
I think that exercise is maybe the most effective way to do that. Need not be excessive. Very brief intense sesions can affect the blood profile favorably.
Of course, it is wise to follow the dietary advice given to diabetics & those with MetS. (Watch those carbs.)
With restoration of a certain amount of estradiol the aim is to prevent a loss of bone density. A more natural approach than a bisphosphonate - LOL.
Dr. Myers prescribed Vivelle Dot estrogen patches for me early on, partly to moderate side effects of ADT. Risk is blood clots, which estrogen can cause!
Long plane flights to and from South Africa, estrogen patches, and prostate cancer created DVTs and pulmonary emboli which hospitalized me for 8 days and introduced me to warfarin.
In the days before Lupron, DES - a synthetic estrogen - was associated with blood clots. But this does not seem to be much of a risk factor for those who today use low-dose DES (~1mg).
In any case, an E2 patch would not be risky - oral estrogen is the problem - & the patch that Dr. Myers prescribed would have been for a very low dose.
The fact is, having cancer increases the risk of clots. PCa alters coagulation factors. A D-dimer test can warn that there is an active clot. Nattokinase can speed up its removal. I had 3 months on warfarin & I hope never to repeat that experience. I switched to Nattokinase 5 years ago & have not had a problem since.
Wouldn't it be nice if, upon diagnosis, a man received a book containing information that otherwise might take a few years to accumulate. You might have worn compression stockings on those flights & stretched your legs every now & then.
(Alternatively, nattokinase to bring D-dimer down ahead of a flight, & a maintenance dose thereafter.)
After all, your clots were life-threatening & somewhat predictable, but the medical profession prefers that we first experience a clot before using warfarin. Warfarin is considered too dangerous to use prophylactically. The CDC says that it is one of the top drugs that take people to the ER.
If while on warfarin you experience severe bleeding, swallow some vitamin K to negate the warfarin.
I have used Nattokinase for many years for prevention. Now with biochemical recurrence after a prostatectomy, ADT and E2 patches are in my immediate future. I am reviewing various Nattokinase products and doses. Can you tell me which Natto product you use/recommend?
I started using Nattozyme when I stopped warfarin. I still had one vein blocked, but my GP was OK with the experiment. I'm still here, so I'm not inclined to switch, but any product that says it is Nattokinase NSK-SD®, 2000 FU should be OK - it all comes from the same place.
For dosage, get a D-dimer test to check for an active clot. Near zero means no clot. A higher number can be due to something else, but with PCa, chances are that it means a clot somewhere. In that case, nattokinase will initially increase D-dimer. When things quieten down, you can arive at a maintenance dose.
You might want to test fibrinogen too. Nattokinase lowers it. I try to be low-normal. It represents clotting potential.
My nattokinase has 1000 FU/capsule and recommends 2 per day. However, it doesn't say NSK-SD on the bottle. I'm familiar with the D-dimer and fibrinogen tests, and have consulted my Oncologist about measuring these when I start treatment. I've researched E2 extensively, including the PATCH study currently going on in the United Kingdom. I will insist on E2 patches when I start ADT (Lupron) to mitigate some of the ADT side effects. I avoid oral E2, due to the first pass through the liver, as that increases the chances of clotting. Still, I want to minimize those risks by staying on Nattokinase. Any risks of taking a higher dose?
Natto itself has been consumed (as a food) for centuries in Japan. I'm not aware of safety issues.
In terms of dissolving fibrin, overdosing would just be a waste of money.
As for fibrinogen, I once dipped below the normal range. Not desirable, so I eased off on the dose.
When I had the DVT, I needed 6 in the am & 6 in the pm - with no side effects.
I have known men with PCa who took one a day - without testing - & were later surprised by a blood clot. Only testing will confirm a good maintenance dose.
My feeling is that one should take what's required to erode a clot faster than it is accruing. A clot is way more dangerous than the caps.
The focus remains fibrin - i.e. clots. We can't measure them directly. However, plasmin & nattokinase degrade fibrin & produce D-dimer, and thrombin turns fibrinogen into fibrin, so fibrinogen should also be of interest.
But are fibrinogen levels irrelevant? i.e. should we be looking at thrombin?
Elevated fibrinogen is an "unfavorable prognostic factor in some malignancies, such as those of the digestive system, gynecologic malignancies, urologic neoplasms, and soft tissue sarcomas." [1]
That's from a recent study that compared fibrinogen & D-dimer in PCa & BPH cases. Too bad they didn't also include healthy men, because:
"Plasma fibrinogen is an acute phase protein and fibrinogen level increases during malignancy and systemic inflammation." & BPH is an inflammatory condition. The two groups had similar numbers.
{For D-Dimer, though, BPH=0.42; PCa=1.09 ug/mL. LabCorp ref. range is 0-0.49. These were blood tests before biopsy. i.e. D-dimer increase is an early event in PCa. Nattokinase should be started at diagnosis. IMO}
Now for your question:
"Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects." [2]
"All subjects ingested 2 capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for 2 months."
"fibrinogen ... decreased 9% ... for the Healthy Group; 7% ... for the Cardiovascular Group; and 10% ... for the Dialysis Group, whereas blood lipids were unaffected by nattokinase."
So when I start ADT and use transdermal Estradiol patches (tE2) for fewer side effects, should I just take the standard amount of Nattokinase (2000 FU) as I have been for many years? Or should I consider taking more Nattokinase to compensate for the small increase in risk of ADT + tE2, and monitor blood clotting factors (fibrinogen, d-dimer, etc.)?
There are many factors in the coagulation cascade. While it would be interesting to check on all of them, I only monitor fibrinogen.
D-dimer is a post-coagulation clot breakdown metabolite. & I check that it continues to be close to zero. (LabCorp doesn't actually report zero, but rather <20.)
It was my understanding that because the transdermal E bypassed the liver it was not a problem for blood clots, Unlike the high dose oral estrogen that was cleared by the liver caused blood clots.
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