Science Round-Up Seconds: Prostate Cancer Special - Are You Going to Die From or With Prostate Cancer? Plus: What Can be Done to Influence This Fate?

Today's SuppVersity article revolves around the question what YOU can do to make sure that the procedure this guy is about to endure is the only thing to be afraid of, when you are going to your check ups ;-)

Let me just get this out there, if you missed an appointment because you were listening to the show live, yesterday, I am sorry. Carl and I actually went "longer than long". What was originally intended to be a one hour show did end being a 125min podcast. That being said, there is little left for the "Seconds" - at least news-wise. So, I decided to kick off today's installment of the traditional SuppVersity Science Round Up Seconds with a quick hit summary of the bottom line of the show. As far as the details are concerned, I would strongly encourage you to download and listen to the podcast. I am not the one to call his own stuff "highly educational", but I guess even those of you who are already well-versed in this issue will find one or another useful bit of information...  

Apropos useful, if you asked me about the one thing you can do to ward off prostate cancer my answer would be "turn to physical culture". Whether you are at risk of developing a form of prostate cancer (PCa) that will have you die or at least suffer from the disease, everybody has in mind, when he thinks about PCa, will not depend on doing A and not doing B. It's, just as so often, a matter of checks and balances. And the things you got to balance are

• 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. (McTiernan. 2008)
  diet,
• exercise,
• sleep, and
• sun exposure

These are the fundamentals and things may in fact be less complicated than many of the numbers I mentioned earlier in the show would suggest. Ok, there is ...

• Don't ignore this post if you are a woman. Most, if not all of the things that help men ward off prostate cancer will also help women to reduce their risk of developing breast and other forms of cancer. A whole foods diet, a reasonable amount of exercise, a lifestlye that tailors to your natural circadian rhythm (learn more) and allows for adequate amounts of quality sleep (7h+ every night) are a MUST for both, women and men who are concerned about developing any form of cancer.
  

  In fact, the way these parameter changed in the course of the last century, is probably the most likely explanation why you may get the impression that developing some sort of cancer is about to become the new normal.
  a 40% risk reduction in advanced PCa for white men consuming a high amount of fruits,
• much to my own surprise no conclusive evidence that veggies are only half as protective as most of us probably thought they would be (think about the heavily advertised effect of DIM in cruciferus vegetables, for example.
• the thing about dairy in whites and meats in black increasing the overall prostate cancer risk by 70% and 80-90% (all meats vs. red meats), respectively
• the "problem" with only whole tomatoes being associated with significant risk reductions and the failure of tomato sauce (likewise pimped as a savior of the average American's prostate in the media) to elicit any effect on the health of your prostate
• an undebatable increase in cancer risk with increasing food consumption (+100% in the third tertile, Rohan. 1995)
• a non-significant association with the risk of developing prostate cancer with high intakes of vegetable oils (+24%; Rohan. 1995)
• a protective effect of saturated fats (-52%; Rohan. 1995) that appears to depend on the population you are analyzing (and I suppose the bias with which you approach the data)
• the protective power of real vitamin A (retinol; -34% for high(er) intakes. Rohan. 1995) and the absence of the latter for carotenes
• etc.

but in the end, all this tapers towards one thing - a dietary prescription that is not much different from the one you read about here at the SuppVersity on an almost daily basis. It is a balanced whole foods diet that is based on a reasonable baseline intake of carbohydrates, proteins and fats. A diet that puts an emphasis on ratios, not total amounts and above all a diet that is able to promote overall health - in mainstream terms, a mixture of the best principles from the two best-established "anti-cancer" diets yielding something you may want to call a Mediterranean, paleo-esque diet.

What's the role of supplements here?

Despite the fact that the word "supplement" already implies that these agents are nothing that's intended to treat, cure and replace, the shiny adds of the multi-billion dollar industry does suggest just that: Don't be fooled. There is probably use in supplements such as

• the usual suspects: lycopene, ginger, pomegrenate, garlic, green tea, curcumin, resveratrol, grape seed extract, milk thistle, DIM,
• methyldonors (choline, betaine, SAM, etc.) and molecules that are important for the optimal function of the methylation cycle (B6, B12, etc.)
• mitochondrially targeted anti-oxidants like CoQ10 --33% reduction in PSA with 100mg in Safarinejedat et al. (2013), 
• "fish oil" and here mostly EPA -- 30% reduction in PSA with 1.2g per day; Safarinejedat. 2013) 
• melatonin (Srinivasan. 2011)
• coffee and coffee polyphenols -- 47% total risk reduction in a recent study by Li et al. (2003); effect was particularly evident in overweight and obese subjects, etc.

but, none of these supplements is a "game changer", let alone able to revert prostate cancer on its own. All that shiny in-vitro data scientists have accumulated for many of the supplements on the above list (and tons of others!) is of little use, as the agents such as resveratrol or curcumin are not going to make it in anywhere similar "petri dish like" concentrations into your blood and right to the tumor to exert their anti-cancerous magic where they are supposed to do it (this is also true for all OTC variants of "enhanced bioavailability" curcumin)... but does that render them useless?

Follow the "Three Simple Rules of Sensible supplementation" (read more)

No, much to the contrary. Most of these "anti-cancer supplements" are either part of the aforementioned diet, already  (e.g. fish, DIM, green tea, ginger, garlic, pomegrenate, tomotoes, watermelon, etc.), or can be part of what Schmitz-Dräger et al. call a "complex diet", when they refer to the overdue "change of paradigm" from single compounds to more complex diets that must be the "starting point of future epdidemiological research" in prostate cancer prevention (Schmitz-Dräger. 2012) - food first, supplements second - and if you chose to supplement, don't lose sight of the "Three Simple Rules of Reasonable Supplementation"

Exercise: Obligatory not facultative!

Contrary supplements, exercise is an obligatory part of the "anti-cancer" lifestyle, of which you should by now realize that it is above all a lifestyle in the most sense. It's not an intervention, a regimen, medication or pill and exercise, in the broadest sense of the word, has to be an integral part and not a doctor prescribed addition to your daily routine. It's not a short term intervention or a quick fix solution and you cannot expect "immediate results". If you start out working out regularly (I suggest to go for at least three and no more than 5 workouts per week), you will be able to reap the fruits of your labor in 10-15 years, when the doctor will stick his finger in your anus and say: "Everything all right Mr Physical Culturist! Absolutely no reason to be worried" (a high fitness level translates to a -64% risk reduction; cf. Olivera. 1996).

You don't want to forget that both exercise and intermittent or alternate day fasting (Varaday. 2008) can help balance the mTOR/AMPK seesaw (read more), and reduce the potential overexpression and overabundance of total and free IGF 1.

Ah, and by the way... whether endurance or resistance training are "optimal" to promote general health and longevity is not a question, simply because both are obligatory. The resistance training to build and maintain muscle mass and the "cardio" training to build (HIIT or HIT) and maintain (LISS) an overall high VO2Max and mitochondrial capacity. That does not mean that you have to run on the treadmill for hours three times a week. But it also precludes going to the gym to sit around "resting" 90% for a "sit your ass flat on the bench and talk with the bros" workout. The latter won't yield a significant glycogen depletion, won't expend significant amounts of energy (-63% risk reduction for 1,000-2,000 kcal being burned during workouts per week; Olivera. 1996), won't increase AMPK (learn more about the "AMPK-mTOR Seesaw"), won't promote autphagy (self-destruction of the cell), won't reduce potentially exuberant IGF-1 levels and won't have beneficial effects on prostate cancer risk.

Don't be scared of your own hormones!

If you pair that with adequate sleep (at least 7h) and light exposure patterns that are both synchronized to your circadian rhythm, there is no reason to be worried about androgens as their effect on prostate cancer is facilitative, not causative (Gershman. 2013), so that even testosterone replacement therapy (TRT) should not pose a problem (Isbarn. 2009).

"Although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression" (Morgentaler. 2013)

In fact, case reports and small scale observational studies from Morgentaler et al. and Rhoden et al. clearly suggest that prescribing TRT is not just save even for patients who have just undergone treatment for PCa, it is even more or less warranted, to "reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications" (Aversa. 2012) and can lead to decreases in PSA even in untreated PCa patients (Morgentaler. 2009)

Does estrogen make women better endurance athletes because it increases mitochondrial biogenesis and gears your metabolism towards fatty acid not glucose oxidation? And if that is the case, would men benefit from some more estrogen, as well? Also, what about muscle building, is estrogen your friend or the foe people want it to be (read more)?

Estrogen therapy for prostate cancer? I guess some of you may have thought I was kiddin' when I mentioned that over here in Europe some MDs prefer using synthetic estrogens instead of anti-androgens as a treatment strategy for prostate cancer. As Carl rightly pointed out, this will likewise shut down the production of testosterone and could prevent many of the unwanted side effects on bone and brain. In view of the fact that the progression from benign to highly malignant prostate cancer is usually accompanied by a loss of estrogen beta receptors on the cells (Gabal. 2007), it may yet even serve a more direct purpose, at least in those cancer cells that are still responsive to the estrogen, where the activation of the E2-beta receptor has been associated with a blockade of cancer progression (Hartman. 2012).

Much related to these results is the increasing interest in the usefulness and superiority of intermittent androgen deprivation therapy as an effective alternative to the classic "eradication regimen" with significantly reduced side effects that may yet not be suitable for all patients (Klotz. 2013).

Can your masturbate your way to a healthier prostate?

Apropos side effect. The total eradication of your libido is unfortunately one of the most common side effects of androgen deprivation therapy - I wonder if that happens to the same extent if it's done with estrogen, but I am digressing, ... so back to the libido thing and Carl's absolute favorite, the protective effects of regular ejaculations: 4-7, to be precise is what a  2004 study by Leitzmann et al. found to be associated with a -11% risk reduction in young and a whopping -51% risk reduction in older men (Leitzmann. 2004). We do yet have to be careful, because

1. We all know (at least I hope so) that two parameters that correlate do not necessarily have a causal relationship, as well.
2. The study participants were almost exclusively European Americans and in view of what we have learned from the Hayes study (1999) about the vast differences various dietary factors have on African vs. European Americans, it is not impossible that ejaculations are like grains: beneficial for fair skinned, but carcinogenic for people with dark skin (again no causation implied ;-)
3. We could be dealing with another case of reverse causation, where early symptoms of prostate cancer (like prostate enlargement) cause pain and will have the subjects reduce their ejaculation frequency; luckily the scientists were smart enough to come up with this possible confounding factor as well:
   

   

   A hefty dose of Tongkat Ali is probably not turning you into a bodybuilder, but maybe into a sex machine (read more).

   "We were concerned about the possibility that the observed inverse relationships were due to avoidance of ejaculation among men with early symptoms related to prostate cancer. However, diminished ejaculation frequency as a preclinical consequence of prostate cancer would be expected to be more pronounced among men with advanced prostate cancer than among men with organ-confined prostate cancer, a circumstance that was not supported by our data.
   
   In addition, our findings were essentially unaltered when we excluded cases diagnosed in the early years of follow-up. Hence, our results suggest that reverse causation may have accounted for very little, if any of the observed inverse association between high ejaculation frequency and total and organ-confined prostate cancer risk." (Leitzmann. 2004)

   Thus, pain and subsequent avoidance of sexual intercourse or masturbation does apparently not explain the observed differences.
4. False reporting could be an issue, but within the same cohort of health professionals other studies checked for the accuracy of the reports and found them to be "reasonably accurate" (Leitzmann. 2004). With the questionnaires being totally anonymous, it is thus unlikely that someone lied about his ejaculation frequency.
5. The study did not measure ejaculation frequency during puberty, so that the results are "generalizable to white US men aged 46 years or older" (Leitzmann. 2004), only.

Nevertheless, aside from the Dimitropoulo study from 2009, the negative results of which I discussed on the air (listen to the podcast), there are 9 studies that observed similar beneficial associations (yet not all were significant), 3 studies where no associations were found and 7 studies in which the researchers observed a significant or nonsignificant inverse relationship.

Moreover, we are still at a loss as far as the potential reasons for the touted beneficial effects. Often heard hypothesis usually revolve around

• HPV infections are unlikely the reason for the downsides observed in some of the studies. More recent studies could not find any evidence of previous HPV infections in "the average" prostate cancer patient (May. 2008; Groom. 2012)
  alterations of the composition of prostatic fluid, a decrease of the intraprostatic concentration of xenobiotic compounds and chemical carcinogens, which readily accumulate in prostatic fluid, 
• a reduced development of intraluminal prostatic crystalloids, which have been associated with prostate cancer in some, but not all pathology studies and 
• endogenous effects of the seminal plasma on the local immune responsiveness that may diminish intraprostatic immune surveillance against tumor cells. 

Even the psychological relieve and relaxation that comes with an organism has been implicated as a potential underlying mechanism for the benefits, as the epithelial cell division in the prostate is stimulated by the release of growth factors from adjacent stromal cells that are heavily innervated with α1 adrenergic receptors (summarized based on Leitzmann. 2004)

Against that background I decided (probably much to Carl's dismay, to kick the "masturbate regularly" advice from the initial list of the four pillars of prostate cancer prevention, i.e. diet, exercise, sleep and a reasonable amount of sun exposure. As far as sex and masturbation goes, the jury is simply still out there.

---

So, do we either die from prostate cancer or die with prostate cancer? Those of you who have listened to the show know the answer already. Your chance to die from prostate cancer is 0.018% (CDC data from 2012). So unless you are one of the 188 unlucky guys among 1 million male US citizens, I gather that your chance of dying with "prostate cancer" (i.e. any form of abnormal tissue in your prostate) is probably 10,000x higher (estimated based on data from Zare-Mirzaie. 2012) ... and so is the chance neither you or anyone else will ever notice.

References:

• Aversa A, Francomano D, Lenzi A. Cardiometabolic complications after androgen deprivation therapy in a man with prostate cancer: effects of 3 years intermittent testosterone supplementation. Front Endocrinol (Lausanne). 2012;3:17.
• Barnard RJ, Ngo TH, Leung PS, Aronson WJ, Golding LA. A low-fat diet and/or strenuous exercise alters the IGF axis in vivo and reduces prostate tumor cell growth in vitro. Prostate. 2003 Aug 1;56(3):201-6.
• Campbell TJ, Tindall DJ, Figg WD. Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer. Cancer Biol Ther. 2012 Mar;13(5):237-8.
• Dimitropoulou P, Lophatananon A, Easton D, Pocock R, Dearnaley DP, Guy M, Edwards S, O'Brien L, Hall A, Wilkinson R, Eeles R, Muir KR; UK Genetic Prostate Cancer Study Collaborators; British Association of Urological Surgeons Section of Oncology. Sexual activity and prostate cancer risk in men diagnosed at a younger age. BJU Int. 2009 Jan;103(2):178-85.
• Gabal SM, Habib FM, Helmy DO, Ibrahim MF. Expression of estrogen receptor-B ( ER-B ) in bengin and malignant prostatic epithelial cells and its correlation with the clinico-pathological features. J Egypt Natl Canc Inst. 2007 Dec;19(4):239-48.
• Gershman B, Shui IM, Stampfer M, Platz EA, Gann PH, Sesso HL, Dupre N, Giovannucci E, Mucci LA. Prediagnostic Circulating Sex Hormones Are Not Associated with Mortality for Men with Prostate Cancer. Eur Urol. 2013 Jan 11. doi:pii: S0302-2838(13)00006-7.
• Groom HC, Warren AY, Neal DE, Bishop KN. No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses. PLoS One. 2012;7(3):e34221. doi: 10.1371/journal.pone.0034221. Epub 2012 Mar 28.
• Grossmann M, Wittert G. Androgens, diabetes and prostate cancer. Endocr Relat Cancer. 2012 Sep 5;19(5):F47-62.
• Hartman J, Ström A, Gustafsson JÅ. Current concepts and significance of estrogen receptor β in prostate cancer. Steroids. 2012 Oct;77(12):1262-6.
• Hayes RB, Ziegler RG, Gridley G, Swanson C, Greenberg RS, Swanson GM, Schoenberg JB, Silverman DT, Brown LM, Pottern LM, Liff J, Schwartz AG, Fraumeni JF Jr, Hoover RN. Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol Biomarkers Prev. 1999 Jan;8(1):25-34.
• Ilic D, Forbes KM, Hassed C. Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008007.
• Isbarn H, Pinthus JH, Marks LS, Montorsi F, Morales A, Morgentaler A, Schulman C. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol. 2009 Jul;56(1):48-56.
• Klotz L. Intermittent versus continuous androgen deprivation therapy in advanced prostate cancer. Curr Urol Rep. 2013 Jun;14(3):159-67.
• Li Q, Kakizaki M, Sugawara Y, Tomata Y, Watanabe T, Nishino Y, Tsuji I. Coffee consumption and the risk of prostate cancer: the Ohsaki Cohort Study. Br J Cancer. 2013 Jun 11;108(11):2381-9.
• May M, Kalisch R, Hoschke B, Juretzek T, Wagenlehner F, Brookman-Amissah S, Spivak I, Braun KP, Bär W, Helke C. [Detection of papillomavirus DNA in the prostate: a virus with underestimated clinical relevance?]. Urologe A. 2008 Jul;47(7):846-52.
• McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008 Mar;8(3):205-11.
• Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009 Feb;55(2):310-20.
• Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. J Sex Med. 2009 Feb;6(2):574-7.
• Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations. J Urol. 2013 Jan;189(1 Suppl):S26-33.
• Oliveria SA, Kohl HW 3rd, Trichopoulos D, Blair SN. The association between cardiorespiratory fitness and prostate cancer. Med Sci Sports Exerc. 1996 Jan;28(1):97-104.
• Rhoden EL, Averbeck MA. Testosterone therapy and prostate carcinoma. Curr Urol Rep. 2009 Nov;10(6):453-9.
• Rohan TE, Howe GR, Burch JD, Jain M. Dietary factors and risk of prostate cancer: a case-control study in Ontario, Canada. Cancer Causes Control. 1995 Mar;6(2):145-54.
• Safarinejad MR, Shafiei N, Safarinejad S. Effects of EPA, γ-linolenic acid or coenzyme Q10 on serum prostate-specific antigen levels: a randomised, double-blind trial. Br J Nutr. 2013 Jul;110(1):164-71.
• Schmitz-Dräger BJ, Lümmen G, Bismarck E, Fischer C. Prevention strategies for prostate cancer. Minerva Urol Nefrol. 2012 Dec;64(4):225-31.
• Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP. Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):109-23. Review.
• Taksler GB, Cutler DM, Giovannucci E, Smith MR, Keating NL. Ultraviolet index and racial differences in prostate cancer incidence and mortality. Cancer. 2013 Jun 6.
• Torti TC, Matheson GO. Exercise and Prostate Cancer. Sports Medicine. 2004; 34(6):363-369.
• Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK. Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice. FASEB J. 2008 Jun;22(6):2090-6.
• Waldert M, Schatzl G, Swietek N, Rom M, Klatte T. Sex hormone-binding globulin is an independent predictor of biochemical recurrence after radical prostatectomy. J Urol. 2012 Sep;188(3):792-7.
• Zare-Mirzaie A, Balvayeh P, Imamhadi MA, Lotfi M. The frequency of latent prostate carcinoma in autopsies of over 50 years old males, the Iranian experience. Med J Islam Repub Iran. 2012 May;26(2):73-7.