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Medical Forum / Diseases and Disorders / Prostate Cancer / April 2008Low DHT increases risk of prostate cancer death
Decreased levels of DHT at the time of diagnosis result in increased risk of dying from prostate cancer. See http://tinyurl.com/3myzz2 Ed Friedman On April 9, Ed wrote: > Decreased levels of DHT at the time of diagnosis result in increased > risk of dying from prostate cancer. See http://tinyurl.com/3myzz2 That 2007 Swedish study concludes, based upon 17 PCa-related deaths out of 41, in a study cohort of 65, "Although the prognostic value of DHT levels at diagnosis remains unclear, these results provides (sic) evidence of an association between low DHT and decreased survival in prostate cancer patients." (Well, there is an association between the cock's crow and sunrise, too.) It is contradicted by every one of the many studies and essays I have read, including this 2008 Mayo Clinic study: Tindall DJ, et al., "The rationale for inhibiting 5alpha-reductase isoenzymes in the *prevention* and treatment of prostate cancer." (emphasis added) It begins, "Androgens are essential for prostatic growth and development but they also have a significant role in prostate disease pathogenesis. Dihydrotestosterone, the primary prostatic androgen, is transformed from testosterone by types 1 and 2 5alpha-reductase and, thus, a potential therapeutic benefit could be achieved through the inhibition of 5alpha-reductase." The operative sentence in the conclusion is, "The inhibition of 5alpha-reductase represents a valid target for prostate cancer risk reduction and treatment strategies." See Pub Med ID 18280514 at www.pubmed.gov Pub Med is a service of the US National Library of Medicine. Regards, Steve J Both pieces can fit together. In aggressive PCa, the tumor cells do not need androgens (or at least not high levels). In low-risk disease, an androgen supply is required. So it is not unreasonable to find that low DHT levels signal advanced disease, and hence the risk of death is increased. Here is a reference to an earlier study that found a similar relationship between DHT and PCa aggressiveness...ron J Urol. 2006 Oct;176(4):1387-91 Association between the dihydrotestosterone level in the prostate and prostate cancer aggressiveness using the Gleason score. Nishiyama T, Ikarashi T, Hashimoto Y, Suzuki K, Takahashi K. Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. PURPOSE: To our knowledge the association between dihydrotestosterone in the prostate and prostate cancer aggressiveness has not yet been elucidated. We analyzed dihydrotestosterone levels in the prostate and Gleason score in patients diagnosed with clinically localized prostate cancer. MATERIALS AND METHODS: A total of 81 patients with suspected prostate cancer underwent prostate biopsy. Serum samples were collected before biopsy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. RESULTS: A total of 47 patients were diagnosed with stages T1 to T3N0M0 prostate cancer and 34 were diagnosed with no malignancy. Of the 47 patients 32 had a Gleason score of 6 or less and 15 had a score of 7 to 10. Dihydrotestosterone in prostatic tissue in patients with Gleason score 7 to 10 disease was significantly lower than in those with Gleason score 6 or less disease (p = 0.025). Gleason score correlated with the testosterone-to-serum dihydrotestosterone ratio (rs = 0.329, p = 0.038). CONCLUSIONS: Patients with Gleason score 7 to 10 prostate cancer have low dihydrotestosterone in the prostate, although there were no significant differences between patients with Gleason score 7 to 10 vs 6 or less prostate cancer with respect to serum androgens. Low dihydrotestosterone in cases of aggressive prostate cancer is probably sufficient to activate androgen receptor expression and propagate tumor growth. PMID: 16952639 On April 9, Ron replied to me: > Both pieces can fit together. (snip) Not when, as I quoted above, "The inhibition of 5alpha-reductase represents a valid target for prostate cancer risk reduction and treatment strategies." And we know that inhibition of 5AR reduces if not entirely stops the transformation of T into DHT. DHT, as I think we can all agree, nourishes PCa cells. Yes, some advanced PCa cells do not require T or DHT to flourish. So what are we being told by the Swedish and the Japanese studies? That lowering DHT by use of 5AR inhibitors will *cause* advanced PCa? That's the implication as I see it, and it is not supported by the evidence. On the other paw, we're told that a low amount of DHT at diagnosis is a sign of advanced disease. How so? What is the causal relationship? They don't tell us. Mainly because they don't know. All they are doing is reporting what they observed; they do not try to explain it. Just another of the multitude of conundrums in this business...... Regards, Steve J Steve...see my comments within your text...ron > On April 9, Ron replied to me: > [quoted text clipped - 7 lines] > not entirely stops the transformation of T into DHT. DHT, as I think we > can all agree, nourishes PCa cells. No. Again, generally speaking, aggressive disease does not have the same androgen requirement to nourish the tumor cells as does less aggressive, or earlier stage disease. > Yes, some advanced PCa cells do not require T or DHT to flourish. So > what are we being told by the Swedish and the Japanese studies? That > lowering DHT by use of 5AR inhibitors will *cause* advanced PCa? That's > the implication as I see it, and it is not supported by the evidence. No. The implication is that low DHT at diagnosis is a warning sign of advanced disease. > On the other paw, we're told that a low amount of DHT at diagnosis is a > sign of advanced disease. How so? What is the causal relationship? They > don't tell us. Mainly because they don't know. All they are doing is > reporting what they observed; they do not try to explain it. Correct, that's often how science works. Initially, someone makes an observation; later work will provide the causal relationship. However, in the case at hand, it is known that the tumor cells in aggressive disease are so dedifferentiated that they don't produce PSA, they don't require T or DHT, etc. The entire tumor machinery is redirected to grow blood vessels and survive on non-adrogenic materials (or extremely low amounts of androgenic materials). There is no need for T or DHT, so the cancerous cells redirect the intracellular machinery away from using/producing these materials. Hence there levels are low. > Just another of the multitude of conundrums in this business...... > > Regards, > > Steve J I'm no expert in any of this, but let me suggest another possible explanation for a correlation between low DHT and aggressive disease. This suggestion is not meant as a theory explaining all phenomena related to this, only as a possible factor that could, perhaps, account for some correlation between the two. Perhaps men with low testosterone and non-aggressive disease don't show up on the radar screen. Perhaps they either don't get cancer, or they usually get it so late in life, or at such low levels, that their physical exams don't reveal anything. On the other hand, if they DO have enough cancer to show up in PSA and other tests, it's because the cancer they have is unusually aggressive, and it grows in spite of the low levels of testosterone. Another way to state this theory is, given a population containing a certain percentage of men with aggressive cancers and a certain percentage with non-aggressive cancers, low T levels will suppress more of the cancers in the low level disease patients, leaving a higher proportion of such patients with aggressive disease. If that theory is right, the correlation between low T and high aggressiveness is not a causal one. Low T doesn't cause aggressive disease, rather it filters out some of the non-aggressive disease. But the aggressiveness of cancers that are detected among men with low T is higher. If this explanation is right, and I have zero reason to believe either that it is or it isn't, we could get evidence for or against it by surveying a random sample of men of, say, a particular age, and carefully evaluating them to find out 1) their T level and 2) whether they have cancer - even small amounts. If my theory is right (again, I'm not proposing that it is), then among ALL men, men with low T will have less overall cancer, and no more aggressive cancer than men with high T. But among MEN WITH CANCER, a higher percentage of men with low T will have aggressive disease. Does that sound plausible? > If my theory is right (again, I'm not proposing that it is), then > among ALL men, men with low T will have less overall cancer, and [quoted text clipped - 3 lines] > > Does that sound plausible? Actually, they have checked into this (Urology. 2006 Dec;68(6): 1263-7), and what they found was for men with low levels of T, the lower the T the higher the percentage of them who were found to have prostate cancer. Ed Friedman >> If my theory is right (again, I'm not proposing that it is), then >> among ALL men, men with low T will have less overall cancer, and [quoted text clipped - 10 lines] > > Ed Friedman My doc was saying that low T was the body's way of reacting to prostate cancer. So, first you develop PCa, then your body lowers T, then your Pca slows down. I'm not a doctor, but I play one on the internet. > It is contradicted by every one of the many studies and essays I have > read, including this 2008 Mayo Clinic study: [quoted text clipped - 20 lines] > > Steve J Steve, You are comparing apples and oranges here. The rationale for using a 5AR2 inhibitor is to increasee the imbalance between the agonism of the membrane androgen receptor (mAR) and the intracellular androgen (iAR), thus increasing the amount of pro-apoptic proteins produced (as explained in my model - see http://www.tbiomed.com/content/4/1/28). The disadvantage of this approach is its increase in the anti- apoptotic Bcl-2 (which is why doing things that further increase Bcl-2, such as taking phytoestrogens, can lead to very aggressive PC as observed by Dr. Lebovitz). When you are not using drugs to create an artificial imbalance in the agonism of mAR and iAR, then the more agonism of iAR, the better. A 20 year study showed that the lower the level of T, the more aggressive the PC was if that man developed PC (the reference is in my paper). Basically, more agonism of iAR translates into lower levels of Bcl-2 - the main reason you don't see PC, even in autopsies, in teenagers. Also, the statements made in that 2008 Mayo Clinic study demonstrate the author's lack of understanding of PC. While he is correct that androgens have an essential role in normal prostate cell growth and development, he is wrong in saying that they have a significant role in PC pathogenesis. There is simply no evidence to support that statement (you don't have to believe me on this - check out the many articles written about this by Dr. Morgentaler of Harvard). In conclusion, in order to understand the role of mAR and iAR in PC, you have to understand the power of balance. As I have stated in my article, if you can create an imbalance between iAR and mAR agonism, you increase the rate of apoptosis. Ideally, once they develop a drug that specifically blocks just mAR, then total antagonism of mAR coupled with total agonism of iAR may actually lead to a systemic cure of PC. Even total agonism of mAR coupled with total antagonism of iAR should be quite effective (which is why Dr. Lebovitz gets such positive results with high T/ low DHT treatments). Ed Friedman On April 9, ed Friedman replied to me: > You are comparing apples and oranges here. Au contraire, I am simply citing authorities that have a viewpoint that differs from Ed's and the authors of the two previously-cited studies. (snip interesting theory) > Also, the statements made in that 2008 Mayo Clinic study demonstrate > the author's lack of understanding of PC. Whoa! It would be well, I think, to check the credentials of a medic before claiming that he lacks understanding of the topic upon which he writes. Dr. Tindall, the lead author, is a professor of biochemistry/molecular biology and a professor of urology. He is engaged in "....investigating the molecular mechanisms by which androgens regulate gene expression in target tissues, particularly the prostate...," according to his bio. His published, peer-reviewed, papers on Pub Med total109. Anyone who is interested can find his academic and professional bio at http://www.mayoclinic.org/bio/10984372.html I didn't take time to look up the co-author, Rittmaster. > There is simply no evidence to support that > statement (you don't have to believe me on this - check out the many > articles written about this by Dr. Morgentaler of Harvard). Please cite a source. Frex, Pub Med. As for Ed's theory, maybe he's right, maybe he's wrong. I certainly don't have a background that qualifies me to critique it. In what peer-reviewed journal is the article published? Regards, Steve J > On April 9, ed Friedman replied to me: > > > You are comparing apples and oranges here. > > Au contraire, I am simply citing authorities that have a viewpoint that > differs from Ed's and the authors of the two previously-cited studies. Steve, Let me clarify what I mean about comparing apples and oranges. Basically, when you lower DHT and couple it with high levels of T, you get much different results than when you lower DHT and couple it with low levels of T. Essentially, no good comes from both low T and low DHT. To illustrate why you must take into account the level of T when you talk about very low levels of DHT, consider what the effect would be when T is below the castrate level. You certainly would agree that effect is different than what occurs from just lowering DHT levels. > > Also, the statements made in that 2008 Mayo Clinic study demonstrate > > the author's lack of understanding of PC. [quoted text clipped - 3 lines] > writes. > Anyone who is interested can find his academic and professional bio athttp://www.mayoclinic.org/bio/10984372.html Again, you misunderstand me. I mean no insult to any specific doctor. However, anyone who puts forth a theory which is refuted by experimental evidence, by definition does not have a correct theory and therefore does not have a complete grasp of the subject. Needless to say, this criticism applies to almost everyone who writes articles about prostate cancer. Also, to criticize an experimental finding just because it doesn't fit one's theory is anti-science. In biology and medicine, properly done experiments are the benchmark that determines what reality is, not theories or widely held beliefs that are inconsistent with the properly done experimental findings. > > There is simply no evidence to support that > > statement (you don't have to believe me on this - check out the many > > articles written about this by Dr. Morgentaler of Harvard). > > Please cite a source. Frex, Pub Med. One of his papers can be viewed at: http://www.europeanurology.com/article/S0302-2838(06)00787-1/fulltext > As for Ed's theory, maybe he's right, maybe he's wrong. I certainly > don't have a background that qualifies me to critique it. In what > peer-reviewed journal is the article published? I'm not sure which article you are referring to. I gave you the reference in my first post of this thread to my most recent paper, published in the peer-reviewed Journal of Theoretical Biology and Medical Modelling. My latest paper, which hopefully will explain things at a level most doctors will be able to understand, has been submitted to the Lancet. > Regards, > > Steve J Again, you don't have to be an expert to evaluate a theory. When it comes to something like prostate cancer, all you have to do is to find a single experiment that is inconsistent with a model and by definition that model is wrong. So far, I have not been able to uncover any experimental finding which is not explained by my model, nor has anyone else (or if they have, they haven't told me). I have been contacted by patients who have asked pointed questions about my model and challenged me to explain findings which I did not cover in my paper. So far I have been able to answer all of their questions. This means that if my model ultimately turns out to be correct, then there are ordinary patients walking around today that understand prostate cancer better than almost all of the big name prostate cancer doctors. Ed Friedman On Apr 9, 11:26 pm, e...@math.uchicago.edu wrote: > > On April 9, ed Friedman replied to me: > [quoted text clipped - 70 lines] > > Ed Friedman Just a shot in the dark - could low DHT levels result from the DHT being excessively taken up by the cancer cells? Lud On Apr 9, 9:19 pm, e...@math.uchicago.edu wrote: > ... Basically, more agonism of iAR > translates into lower levels of Bcl-2 - the main > reason you don't see PC, even in autopsies, in > teenagers. ... If cancer is brought about by an accumulation of mutations in DNA then, for many cancers at least, wouldn't you expect to find a strong correlation between age and cancer? Alan > On Apr 9, 9:19 pm, e...@math.uchicago.edu wrote: > [quoted text clipped - 9 lines] > > Alan Alan, An article by a group of Johns Hopkin doctors looked into the growth rate of prostate cancer and calculated when the first prostate cancer cell typically arises. They determined that the age when this happens was in the 20's and 30's (http://clincancerres.aacrjournals.org/cgi/ content/abstract/1/5/473). By coincidence this also happens to be the time when total bioavailable levels of T start to drop in men due to the increase in SHBG. Also, in order to get the mutations necessary for cancer to occur, it helps to have uncontrolled cell growth, since the more inappropriate cell divisions that occur in any tissue, the more likely that the exact mutations that are needed to cause cancer will occur. In the prostate, high local levels of estradiol are all that is needed to start the uncontrolled growth of prostate cells, and this can happen at any time following puberty. Ed Friedman On Apr 14, 9:03 am, e...@math.uchicago.edu wrote: > > On Apr 9, 9:19 pm, e...@math.uchicago.edu wrote: > [quoted text clipped - 29 lines] > > Ed Friedman Ed What are the readings for DHT - it is many times more potent than T. With low T and high SHBG, it is definitely possible to have very high DHT levels. If the DHT levels are not studied then the paper is incomplete and no conclusions can be established. From my experience on high dose Casodex, I had T in the upper reference range, SHBG was above reference range, my estradiol was above the reference range and my DHT was way above the reference range despite the 60% reduction by Proscar. In my case, I believe, the DHT was the dominant reason for my PSA rise of my androgen dependent PCa. Lud > On Apr 14, 9:03 am, e...@math.uchicago.edu wrote: > [quoted text clipped - 45 lines] > > Lud Lud, The median level of DHT was 0.67 ng/l. The median level of DHT for those who died of PC was 0.54 ng/l. The median level of DHT for those who did not die of PC was 0.79 ng/l. Ed Friedman On April 14, Ed Freidman replied to Lud, in pertinent part: > The median level of DHT was 0.67 ng/l. The median level of DHT for > those who died of PC was 0.54 ng/l. The median level of DHT for those > who did not die of PC was 0.79 ng/l. Which means exactly nothing regarding the alleged "association" of 5-alpha reductase inhibitors with advanced PCa. Somehow, I can't drill into certain heads the fact that "association" (remember the cock & sunrise) does not prove, nor is it evidence of, a causal relationship. I can hardly balance my checking account, but by God I know how to evaluate evidence. Regards, Steve J > On April 14, Ed Freidman replied to Lud, in pertinent part: > [quoted text clipped - 15 lines] > > Steve J Steve, I was saying nothing about any "association" of 5AR inhibitors and advanced PCa. The DHT levels were what were observed at diagnosis for PCa. Those men with lower DHT levels at that time were more likely to die within the next 15 years. Either this is just a coincidence or more aggressive PCa lowers DHT or low DHT causes more aggressive PCa. I believe that the last choice is the most likely, simply because (as I explained in my model) lower DHT results in higher levels of Bcl-2, which by definition (all else being equal) makes any PCa more aggressive. If you have reasonable explanations for how this could be an unrelated coincidence or how faster growing PCa can lower the entire body's DHT level, then you are free to put them forth. Although no mention was made in the paper, I strongly suspect that those men with lower DHT also had lower levels of free T. Ed Friedman >Decreased levels of DHT at the time of diagnosis result in increased >risk of dying from prostate cancer. With apologies to you Ed, and Steve and Ron for interrupting the flow of the thread. I have been totally unable to follow the cut and thrust of what is a high level academic/technical argument. But I would like to distill down to the one post I could understand - Ed's orginal - above. Assuming Ed, for the moment, your statement is correct. The body also refers to high Gleason as increasing mortality likelihood. I was diagnosed Gleason 9. I am now T3c NI M0. Prostate and left seminal vesicle primary sources ablated (HIFU) - but now lymph node involvement. So my next step will be hormonal therapy. I am 81 in November. The study is valid. You're me. Would you go for HT? Theoretically? With much thanks MikeHi On Apr 10, 5:30 am, Mik...@anon.co.uk wrote: > >Decreased levels of DHT at the time of diagnosis result in increased > >risk of dying from prostate cancer. [quoted text clipped - 20 lines] > > MikeHi Mike, I'm not an MD, but hypothetically, if I were in your situation, I would opt for slowing down PSA velocity along with maximizing quality of life. Basically, if you look at Dr. Leibowitz's case histories for men treated with high T/low DHT, at http://www.compassionateoncology.org/pdfs/TRTcase_reports_03_07.pdf, then patient #5 opted for high T/ low DHT without doing HT first (which is what I would opt for personally). Note that for this patient, his PSA doubling time was greater than 15 years. I'm sure that almost everyone in this group would be happy to have such a PSA doubling time. Of course, the problem is that at presently it is probably impossible to find a doctor willing to treat you this way. Hopefully, this will change after my next article gets published, but it will still take time. Ed Friedman MikeHi writes: >> >Decreased levels of DHT at the time of diagnosis result in increased >> >risk of dying from prostate cancer. I wrote to Ed asking: (snip) >> I was diagnosed Gleason 9. I am now T3c NI M0. Prostate and left >> seminal vesicle primary sources ablated (HIFU) - but now lymph node >> involvement. So my next step will be hormonal therapy. I am 81 in >> November. >> >> The study is valid. You're me. Would you go for HT? Theoretically? Ed has just replied to me as follows: >I'm not an MD, but hypothetically, if I were in your situation, I >would opt for slowing down PSA velocity How, if no HighT treatment available? My PSA January 23 2008 6.0 (Aug 2007 -Jan 2008 PSADT 0.9yrs PSAV 4 ng/ml/yr). >along with maximizing quality >of life. At my age, certain recurring aspects of QQL the study patients celebrated, like libido, may unfortunately be kept from my eager grasp by that humourless bloke preparing the scythe. My priorities are rather more, not getting all sorts of new body problems. If it's possible. >Basically, if you look at Dr. Leibowitz's case histories for >men treated with high T/low DHT, at http://www.compassionateoncology.org/pdfs/TRTcase_reports_03_07.pdf, [quoted text clipped - 3 lines] >that almost everyone in this group would be happy to have such a PSA >doubling time. The rapid rise in his testosterone levels over the years accompanied by almost stable PSA for #5 looks remarkable to my lay eyes. But in the UK, in my limited experience as a patient, no doctors look at testosterone levels on their own. I certainly don't have a clue what mine are. And there is no likelihood, as you note of high T treatment being accepted anywhere 'real soon' :-) Looks like I might have to mess around (stop start, see how it goes) with HT and all its question marks- only way I can see at moment to buy time rather than let PSA and stuff runaway. >Of course, the problem is that at presently it is probably impossible >to find a doctor willing to treat you this way. Hopefully, this will >change after my next article gets published, but it will still take >time. Ed, I do not have the expertise to judge whether you're right or wrong; you certainly have evidence. But I wish you the greatest success on publication of your paper. I remember. many many years ago as a very young man, before I became wise with a beard, being instrumental in introducing very new technologies into the market place. Some failed not because they didn't work (they are now commonplace) but all the managers and experts at the time, the best in the land, knew that abacuses and slide rules and messengers did. You are doing something perhaps even more difficult - following up leads first aired more than 50 years ago - which in modern science terms are when the dinosaurs roamed. You like it tough. My very best wishes, and thanks for your advice. And my best wishes to all. Mike Hi |
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