Bipolar Androgen Therapy (BAT) and CRPC

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

ncbi.nlm.nih.gov/pmc/articl...

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  • 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?

  • The Body and cancer cells do not recognize the load of outside Testosterone---the Pca cells basically drown in it., in very high doses. In one Clinical Trial, in the conclusion: over 50% of the men had between 50-90% reductions in PSA, over a short cycling period---they described the remaining Pca cells in the blood when examined under electronic Microscopes, as appearing to be dirty old men sitting in beach chairs watching the girls go by. In other words the remaining cells that did not die were exhausted.The history at least goes back before Dr. Leibowitz work, which he began in 1997. Do the cancer cells actually feed on or wake up to T, or is it the breakdown metabolites of T that is the real danger. One of the reasons some Patients do well in my opinion is that they are on a triple blockade, of 5-alpha reductase enzymes. These enzymes cause the metabolism breakdown components of T to take a different path, in their breakdown. Read Dr. Zeligs' works. Do a search. He favors the use of Dim [Di-indole methane as his main enzyme] he is published at NIH--but I cannot seem to be able to find his latest papers from this year.

    It is absolutely true and proven beyond a doubt that Low T leads to Pca--and it is accepted by most modern Oncologists and Urologists. Not everyone with low T gets Pca. But those that do a great many had low T whether they knew it or not. I am one!

    Nalakrats

  • Nalakrats , what constitutes the triple blockade ? is Di-insole methane of them or the only one ?

  • The triple Blockade to stop 5-alpha reductase enzyme action on T, and DHT, is Avodart, Proscar, and Dim[Di-indole methane].

    Nalakrats

  • As to DIM you need to read about BioResponse, Dr. Michael Zeligs, I have forgotten on past responses to spell Zeligs correctly. He is published at the National Cancer Institute. His Micro encapsulated Dim is the only Dim used in clinical trials---this Dim at BioResponse, is known to offset Estrogen in men with Pca, in such a way as to safely rid it from the body. His papers will show the relationship between Dim, Estrogen and Pca.

    Nalakrats

  • 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?

  • ? 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,

  • 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.

  • Well it is complicated, because we appear to be dealing with a set of opposites. Point one is a just about an absolute. Proven by taking Biopsies of men with very normal PSA''s --like 1-3, who have T levels less than 300, and digital exams are perfect. 20% of these men, in studies, had Prostate Cancer, as determined by the Biopsy--not a PSA or a Digital exam. These cancers were deep, undetectable and very aggressive. So do you then go to the next step and wait until the PSA starts rising. And now you can be in trouble, if it gets out. One Urologist, from John Hopkins, now retired, gave his patients over 55 years old Blood Tests for T. If they were considered low T, he convinced them to have Biopsies, with normal PSA's--his studies showed 19.8% had Pca.

    Give you an example---A Barber who cuts my hair had a routine PSA at age 59. It was 1.2. This was in 2014. In 2015 his PSA was 2.1---very normal---but his Urologist in Spartanburg was suspicious, as he was a believer In the low T theory. Took his T and it was 305. Immediately did a Biopsy, and found aggressive cancer. Surgery cured the situation--gone. This man is cancer free because someone understood the effects of low T.

    So I ran this thru my Urologist, and he said back to me--Yep, Yep. And I asked, why if he knew this, why did he not follow a similar protocol. Well you know the Answer--insurance and Medicare would not pay.

    As to number 2] Increasing T--We have people here and in the Literature, calling it TRT[Testosterone Replacement Therapy]. Well in my opinion, having been taking T supplementals from 1993 to 2015, I have just a bit of knowledge enough to be what you call dangerous.

    FIRST, there is in my opinion no such thing as replacement T therapy. What you are doing is adding T from another source. Blood tests will say you have now added more T--but I say you did not replace what once was. It is like you always used an Ash wood Bat in Baseball. All of a sudden Ash was not available--so you got Elm wood. You could still hit the baseball like always, but the feel was different something was not the same. Wood is Wood--or is it? So if I could get explicit, You add T to your Low T Body and now you can get great erections and perform as a 25 year old, lift weights like Superman and build muscle. Well there is a whole class of Steroids, mostly man-made that will do the same thing, and they are not T.

    Your body did not make the T you added, so it is a foreign substance. Do not care if it is artificial , natural or Nature Identical--the body did not make it so it does not belong to the body. And the Bodily Mechanisms know it!! So when contemplating T, as I am, for later treatment, I am in a very cautious mode. He have data all over the place, from occasion cures, to remissions, short and long term to Death. The Added T is not replacement it is a drug at high levels. Now the worrisome part is what happens to the added T--can it become a food for your Cancer, can it wildly go to DHT, which is super food for your cancer, or can the Body metabolize the Estrogen bi-products in such a way as to cause no harm.

    Well I can go on and on. But Suggest People find Dr. Michael Zeligs recent papers now at the National Cancer Institute. This Urologist treats patients with T, but he also uses high doses of DIM. I have not read his works in awhile--he sent me about 40 pages of his studies. He maintains men on 30, 40 and higher PSA's with CRPC and they have been stable with their high PSA's, with no further progression. He believes the secret is in controlling how the T gets out of the body by certain chemical pathways, controlled by DIM, which is protective, against further spread---Suggest you find and read his NCI paper.

    As finishing up on my use of cause and effect. Back long before they had PSA tests--an interesting Pathology Study on Cadavers of men who had died of Prostate cancer, with their Prostates intact, were autopsied.

    This was done by Sloan Memorial--and the paper is so old it is most likely lost or the results are in peoples heads. You see we treat the effect and not the cause. Every treatment protocol is treating the cancer with something. How about treating with something before cancer arrives. Treat what will be the cause that leads to the effect [Cancer]. Or if you can obtain a remission, treat the body with something that goes after the cause before more cancer cells show up, as opposed to going on to the next more expensive treatment against the effect. This is where I I believe the answers are to be found.

    So what did the Sloan Memorial Pathology tests find--it would blow you away--sorry I did not have the comparison numbers just the facts. All cadavers, had the Prostates removed--and this was in the multi-hundreds. Upon examination of all removed Prostates they found enormous amounts of Estradiol. So much so, that it appeared the men were taking Estrogen. They concluded further that somehow the Estradiol was the causation of the deaths. But back in those days they could not follow the Chemical Pathways, and research money ended on the project and it died.

    So as to cause and effect, I will ask a Question, that I cannot answer. What is it with men who have Low T that causes them to produce large amounts of Estradiol?

    Nalakrats

  • 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.

  • Sorry Martin but your Chemistry, has to go beyond 49 atoms. Do you know the terminology of Isomer Molecules. That is where we have 2 duplicate molecules, but one is twisted on a different plane from the other. For Example if you take regular Vitamin E---you will see DL Tocopherol. So the Molecule of equal atoms exists on 2 different planes. The L form is totally inactive--meaning the body does not recognize it, because its angle is different than its twin D form. The D form is recognized and has nutritional value and the body uses it. If you buy Taurine, the active form is L. Alpha Lipoic acid comes in RS forms. The R is active and the body uses it. The S is not, and is wasted. You would need to be a molecular Chemist, to determine at how many points along the main axis of the created man made T molecule is twisted in its plane, There could be more than one Isomer twist in complex molecules. Some of it may be active and maybe none of it, relative to its availability to affect prostate cancer. This area is outside of your and my capability to exactly know, since so many ways to make T exists. And each synthesis can produce the same molecule on yet other planes

    I ain't playing chemist with amateurs---I have 87 credits and 3 Degrees in the Subject, along with 7 publications. Granted I have been away from it for years--but some advanced basics remain. Sorry to be lacking enough Knowledge.

    Nalakrats

  • 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.

  • Fascinating stuff, Nalakrats. Sorry your urologist wasn't like your barber's.

    Neal

  • 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.

  • Follow the Estradiol--Work the Metabolic chemistry backwards and you may find the answer you seek. Find how Estradiol gets out of whack, and produced in large amounts, and you will find that what ever does it--has a signal turned on by your Hormonal System--and then more so if presenting Low T.

    For us with Pca it is too late to go back and prevent it. I think some know how to prevent Pca--I have my own Protocol--but I cannot prevent what I already have--the idea now is to kill it.

    Nalakrats

  • 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 !

  • Wagscure--sorry about your side affects:

    There is no way I would allow any Estradiol to come near me. But that is me. I am not a Doctor of Medicine--maybe a Doctor of something else.

    Let me provide some things I do:

    1] For preventing Bone Density Loss, I use a combo of Calcium/Magnesium/Phosphorous Chelate, Boron chelate every other day, Potassium Chelate, and Zinc Chelate--which is my Mineral Stew. I use a Vitamin K1-K2 complex, and The K1 is a transporter of calcium to the bone. I forgot maybe its the K2---but the other K likes to kill Pca in the blood if it comes in contact with a Pca cell. You cannot take the K, if on blood thinners.

    1A]---Going to the gym and working out with weights even though your T is low and using the Machines--helps keep what you have. At 71 I was pressing easily 360 lbs. After Pca, and at 73, I am still at the same gym weights with No T in the Body--I do not Build muscle--just maintain what I had. And the weight bearing is great for bones.

    2] As to mental Acuity I use 1,000 Mg of Acetyl L-Carnitine/day. Even the Mainstream doctor shows on TV recommend it.

    3] In my opinion since I am also a 5-4 Gleason, on ADT, I might want a new modern up to date Doctor. I use what is called a Vantas Implant in my arm. It puts out a Known amount of Lupron every day. It can stay in the arm for a year or more. So there are no highs or lows from shots. The high load when getting the shot and then the low load as you get ready for the next shot. I take 50 Mg. of Casodex, along with Avodart, and Proscar. You get very minimal side effects, as to night sweats, and chills. Now you may be ultrasensitive--but in my case my T levels from Supplementation before the Pca was between 700-800, and I was on it for 22 years---so if anyone should have had a bad time with the Lupron it should have been me. But this daily infusion from the implanted capsule, I was told would offset the night sweats. Once in awhile for 2 minutes I get a little something, but when doing things like blogging it goes unnoticed.

    It is known by some how the estradiol comes to be, and get out of whack, as to Pca. I could write a dissertation on the subject. This does not cure what we already have--but I believe there is something, all men could take after a certain age that would prevent Prostate Cancer in most subjects--like taking an aspirin a day. It would be costly--but with competition, making these items, it could be affordable for most. By the way I get my supplements from Vitacost.com--if you need suggested dosing let me know.

    Nalakrats

  • 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?

  • Gus happy to get 17---that takes me to 90. Your still not on the track to the cause and effect, rational equations of the disease modalities. Your still treating the effects and not the causes. 12 more days till fishing. Saw our mutual friends' Urologist yesterday---says I will definitely make at least 10 years--was a bit disappointed, that he would say that. So 30 years is probably out.

  • 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

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