I like the retionale here : Supraphysiologic androgen replacement induces death in the subsequent cell cycle and the subset of CRPC cells that survive by down regulation of their high AR expression become vulnerable to apoptosis when re-exposed to ADT...the question is how many times can this be repeated...it has the potential to turn PCa into a chronic disease that won't kill you, or put another way, Nalakrats could keep fishing for another 30 years.
Gus
The assumption, though, is that a lot of extra T will kill the prostate (cancer) cells. Not clear what the mechanism would be for this, or what the historical basis is. One might say that it will help any surviving normal prostate cells, that need more T to wake up and re-produce. but that is a longer game.
And related to that is the idea that low T is one of the environmental factors that allows prostate cancer to emerge. I think that is true, but is it something that is accepted?
If there is a connection between low testosterone levels and the emergence of 3+4 prostate cancer, then it may be possible, during active surveillance, to prevent or delay progression by the maintenance of adequate testosterone levels. No?
good (detailed) article though. Thanks. Denmeade again, w/o Antonarakis.
First reaction to the first part of the article: the argument (if true) supports supraphysiologic androgen levels, but is talked about as if it supports BAT, the cycling of testosterone levels. And high T would kill all prostate cells, it seems, not that that would be an unacceptable thing. No?
Nalakrats , what constitutes the triple blockade ? is Di-insole methane of them or the only one ?
? goals of triple blockade - my impression so far sort of.
1. Block the excretion of T into the blood from the testes
2. Block the AR receptor to prevent the transportation of T.
3. Prevent the creation of DHT from T
4. Block the excretion of T into the blood from the adrenals,
From the article, a sentence that seems like a dangerous assumption: " This explains why serum prostate-specific antigen (PSA) does not correlate with serum T concentrations in a normal population,"
First, what the sentence means:
The claim and conjecture: the administration of testosterone seems to be safe in some men. It does not cause prostate cells to become more active. This must mean that the prostate cells can use only-so-much testosterone, so increasing the blood levels past that point can have no effect on metabolic rate - the rate of any biological process, and specifically of cell division, if the rate of cell division is correlated with the rate of PSA production, implicitly invoking a hypothetical "metabolic rate".
Second, they give an observation from the natural world that seems to support this claim and conjecture, since all claims must hop over the low bar of having at least some supporting observation:
Men's PSA, (one of) the output(s) of the prostate cell is not in step with the blood level of testosterone, so testosterone cannot be the sole control of the (the!) metabolic rate.
That is, they are noting that it is (widely) observed that men with diiffering testosterone levels have the same PSA, and they claim that the reason for this is that the men with higher levels, have testosterone in excess of what the prostate cells can use.
This seems to be kind of a weak story.
1. Blood levels of T may not correlate with cellular levels of T. It is the cellular levels of T that would be more likely to control any biologic rates. The purpose of the Androgen Receptor is to increase the concentration of T in the cell over the concentration in the blood, so that simple diffusion is not the transport mechanism. The concentration in the neucleus is anoher question. The number of Androgen Receptors (pumps) on the cell membrane is variable.
2. The "excess testosterone" hypothesis could be tested easily by reducing the testosterone in men they think have "excess testosterone" and seeing if that affects PSA. They predict it will not. Chances of that being true - not good.
3. PSA levels in the blood is not the same as PSA levels in the prostate. PSA in the blood is probably due to "leaks". PSA in the blood may measure only how leaky the prostate is, how damaged the encapsulation is, or the extent of neovascularization. My impression is that healthy glands in normal men do not have lots of blood vessels. The PSA as well as seminal fluid, also created in the prostate, does not normally exit into the blood stream but into the urethra. Blood levels conceptually should be zero.
Then look at the footnote that immediately follows this senterce.
It has the incomprehensible idea that if you have two variables that measure different things (are not highly correlated values), you cannot use one to help understand the other. What can you make of this? Are we to suppose that if you have two measurements of the same thing, that is more useful? Which is more useful to a doctor: knowing heartrate and termperature, or knowing temperature by using two thermometers? Bizzare
Here is the foot note, in case you are not that interested
ncbi.nlm.nih.gov/pubmed/754...
centigrade and farenheit
Nal - I think you are saying that
#1. Lower testosterone *does* increase the odds for PC, and
#2. Increasing T artifically will not decrease the odds for PC.
This structure of facts, if true, looks like the case where PC and low T are both the effects of the same (unknown) cause, rather than cause and effect.
Point #2 is what I understand from your statement "the Body and cancer cells do not recognize the load of outside Testosterone", and I interpret it to mean that exogenous testosterone is not "the same" as endogenous, although low endogenous T *is*causative.
Is that what you mean ... . puzzling.
We see eye to eye on #1. Very much so.
But on #2, you say,
T from another source is not "the same" as T from your own testes. You say it in a few ways, but that does not help.
Testosterone is a compound, C19.H28.O2, composed of 49 atoms, and there is no theory that explains how the body can tell the difference between two molecules of T. So you have to very much more than repeat it; you need to at least be aware that it is a strange claim, and not compare it to wood, as in a baseball bat.
Whether the T is foreign or domestic is not relevant, or at least you need to show how it is relevant. Exclamation marks don't help!!
You go on and say more, but that much is all that this response is about, for now.
So I was reading your resonse to see what you thought about preventing or delaying prostate cancer, by preventing low testosterone. What I got from your response is that you dont think that can work, because external T is somehow different biologially from your own T.
Thanks for answering, but I dont think that that answer is sufficiently justified. Then you go on and add other interesting things about testosterone manipulation more generally.
Well.. you say (and I believe)
20% of Men with "T levels less than 300 ... had Prostate Cancer"
Only 20%. So T<300 is not a necessary and sufficient condition for prostate cancer. There is at least something else, and low T may not be a cause at all, but low T may be the effect of this "something else".
It does make sense however that low T would select for cells that have a greater number of ARs on the membrane. So there is a mechanism in the ballpark. Confusing.
After having read your reference this study at Sloan in the past I asked my medical oncologist there if he was aware of this study ( he is primarily a research scientist MD PH.D. only seeing patients one day per week ) and he was unaware of it . He did put me on an Estradiol patch for cognitive decline , the severe hot flashes , and night sweats with an added bonus to reduce my osteopenia stating that the ADT also reduces estrogen levels , but I took my self off of it due to breast tenderness and a slowly rising PSA since I went on it . I am stage IV , Gleason 5+4 on ADT since 2/13 . Thanks for your excellent discussions at the chemical level !
As you suggested, I read Zelig's papers, as well as visiting his Bioresponse website. My boyfriend has metastatic PCa, diagnosed 2009. Gleason 4+4 and PSA 18, so he had a prostatectomy and radiation. He has been on Lupron ever since. PSA currently .2 on Lupron. His oncologist (MD Anderson) thought she saw some possible lymph node (near spine) involvement on his last scan, but she said nothing to panic about, that she felt that the Lupron would control it. The DIM sounds like a valuable addition to our fight...
On another note, this summer his PSA commenced to rising rather rapidly. After the shot (6 month shot-June 1) his PSA dropped from 4.2 to .03, but by August 1st was 1.2 and Sept 1st was 1.6. On October 1, he decided to try something that had allegedly cured a friend's lung cancer, an herbal remedy containing Bloodroot (Sanguinaria canadensis) and zinc. I've used it for years on horses for Sarcoid tumors, but externally. In any event, 3 days after he started taking it (orally), his PSA was down to .5, and on November 8 it was .2 (which caused much confusion on the part of the oncologist). We are cautiously optimistic as we wait for the next PSA. There are over 30 articles on NCBI about the effect of Sanguinaria on PCa. Have you heard about this?
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