Wednesday, November 19, 2014

Will Even Normal Testosterone Levels Increase Your Cancer Risk? Recent Study Makes it Sound Like it - At First Sight!

Don't fall for someone who overgeneralizes, misreports or -interprets study results to tell you that healthy mid-range testosterone levels were a major trigger of cancer development.
I just got an email from my good friend Carl Lanore who hosts the Super Human Radio Show I am sure you have already seen in the sidebar of the SuppVersity. He pointed me towards the results of a recent study from the Copenhagen University Hospital saying "Adel have you seen this? I'm sure the media will be all over it." Since Carl is usually pretty good at identifying things that "news" make headlines, I would like to leapfrog the mass media craze before any of you consider cutting off their best parts to end up in the allegedly healthy depth of quasi zero testosterone.

You have no clue what I am talking about? Well, I am about to elaborate. You just have to stay with me for the rest of a comparatively long, but insightful (I promise) analysis of the study and related contemporary evidence.
If it's not testosterone it's usually meat that's blamed to increase your cancer risk.

Meat-Love: You May Eat Pork, too!

You Eat What You Feed!

Meat & Prostate Cancer?

Meat - Is cooking the problem

Meat Packaging = Problem?

Grass-Fed Pork? Is it Worth it?
So, where do I begin?  The "mass media compatible message" of the abstract (and this is usually not even as far as most headline producers read) says: Having normal testosterone levels increases your risk of dying from cancer before your time by at least 30%! The more testosterone, the likelier you will pass away before your expiry date."

Well, as I said, this is the mainstream interpretation. And interpretation anyone could identify as being fundamentally flawed by simply reading the abstract carefully. In fact, you don't even have to read the whole 268 words! It would suffice to read the end of the first line of the result section, where it says:
"For risk of early death after cancer, for men [...]" (Ørsted. 2014)
Did you notice it? There is an "after cancer" in this sentence. This means, your risk of dying, if you develop cancer is increased, if [whatever follows]. Now, that which follows is ...
  • if you are in the 2nd quartile, your risk will be increased by 30%,
  • if you are in the 3rd quartile, your risk will be increased by 31%,
  • if you are in the 4th quartile, your risk will be increased by 52% and
  • if you are in the 5th quartile, your risk will be increased by 80%.
So, if you happen to be unlucky enough to develop cancer and your testosterone levels are high there is in fact an increased risk you could die from cancer.

So testosterone is still bad, right? Yes, but anything that is "anabolic", i.e. promotes the growth of all cells in your body is "bad" for someone who has cancer. Guess what chemotherapy will to do your testosterone levels and the amount of other pro-anabolic factors in your body? It will wreak havoc on your testes (Wallace. 1997), reduce their size to that of dried raisins, increase your risk of gynecomastia and reduce your testosterone levels to exactly those 6-10 nmol/L (Whitehead. 1982) of which the previously cited study by Ørsted et al. found that they are associated with the least risk of dying from already existing cancer in your body.
Figure 1: If you look at a random assemble of the myriad of risk associations that have been established for low T, the results of the study at hand do no longer appear to be that frightening - right?
A result that conceals the established negative effects of having low testosterone (see Figure 1) or depressing it which androgen deprivation therapy which may reduce the testosterone levels to the allegedly desirable range, but is associated with a 350% (!) increased risk of dieing from cardiovascular disease in prostate cancer patients (Tsai. 2007). I guess this should make you reconsider the "usefulness" of low testosterone levels.

But there is also an increase in cancer risk, no?

Yes, there is. According to the scientists it is (I quote) "1.07 (95% CI 0.98–1.18) and 1.06 (0.93–1.22) for men and women" if you compare say a man with 10nmol/L to a man with 20nmol/L. Now, as far as I can remember a 95% confidence interval, which is what you see in brackets, i.e. for men 0.98-1.18, defines the range in which the chance that the hypothesis that is tested, i.e. "testosterone influences the risk of prostate cancer" has a 5% chance of not being bullocks... ah, I mean statistical significant.
You really got to look closely: A statistically significant association between an increase in cancer risk for men was found only for oral cancer. Not for lung, prostate, colon, bladder, pancreas, stomach, blood (Leukemia), skin, oesophagus, kidney, larynx or liver. And while the increase in cancer risk for the highest vs. lowest quintile for oral cancer was high (60%), knowing that the same limitations, i.e. no adjustment for family history of cancer (which increases the risk by 160% | Garavello. 2008), diabetes (which is more than 2x more common in patients with diabetes | Ujpál. 2004), etc. (see list below), apply all results of this study, helps to put the "shocking" results into perspective and to read any upcoming media hype with the necessary calmness.
So, the scientists are 95% sure that a 2x higher testosterone level will be associated with a 2% decrease and 18% increase in... does this ring a bell? Yeah, that's not exactly a reliable prediction considering the fact that the researchers adjusted for smoking status, cumulative smoking, body mass index, alcohol consumption, level of education, and level of income for men and women, but "forgot" to adjust for...
  • family history of cancer, which is one of the, if not the main correlate of your risk of developing various cancer, such as prostate cancer (1000% increase, no typo | Steinberg. 1990), colon cancer (up to 59% risk increase depending on the region | Slattery. 1994) or breast cancer (145% risk increase with first-degree relative having breast cancer | Slattery. 1993) 
  • diabetes, which has been found to be associated with a 60% increase in colorectal cancer risk in patients who have been diagnosed with diabetes 10+ years ago (La Vecchia. 1997), a
  • the level of visceral fat, where high levels (relative to total body fat) are associated with 850% increased risk of breast cancer (Schapira. 1994) and up to 1000% increased prostate cancer risk (Hafe. 2004)
  • low sleep duration and quality, which has been associated with an increased risk of developing almost every form of cancer you can think of (Blask. 2009), including 60% increased breast cancer risk for women working the "graveyard shift" (Davis. 2001)
I could go on with all sorts of nutritional factors, medication (specifically hormonal contraceptives) the amount of exercise, the area you live in, your year of birth and hundreds of other factors that have previously been associated with an increase of cancer risk, but I guess the above should suffice to make you less confident that a "confidence interval" of 0.98–1.18 in men and 0.93–1.22 in women was enough to make the claim that "having a high testosterone level would [mechanistically!] trigger the development of cancer.
A general word on the androgen hypothesis of cancer: "Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer," says a 2006 review by Jean-Pierre Raynaud and goes on "[... a] study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone." (Raynaud. 2006) Or, as Morgentaler put it: "there is not now—nor has there ever been—a scientific basis for the belief that T causes pCA to grow" (Morgentaler. 2006)
Bottom line: Never freak out about the results of a single study. Specifically, if you have only read about it in "second" or "third hand" information sources like science magazines, blogs or the mainstream media. Testosterone is a welcome scapegoat, because it distracts us so nicely from the real culprits: Genetic disposition, and most importantly diabetes, being fat (not just overweight) and leading an overal pro-carcinogenic lifestyle as 90% of the inhabitants of the Western Obesity Belt (USA, Europe & Co) do. I mean, if we accepted that the latter were to blame (i.e. everything except genetics), this would mean that each of us would have to do something against it and "doing something" is is not exactly popular. Specifically, if "it" includes working out, eating healthy, practicing sleep hygiene and all those nasty thinks that are totally against our drive to make everything as "convenient" as possible.

Ah, and did I actually mention that I have repeatedly written about studies that show that normal and even high normal testosterone levels are not associated with an increased cancer risk - not even for the prostate (Stattin. 2004; Morgentaler. 2006; Roddam. 2008)? No? Well, now you know it, anyway ;-) | Comment on Facebook!
References:
  • Araujo, Andre B., et al. "Endogenous testosterone and mortality in men: a systematic review and meta-analysis." The Journal of Clinical Endocrinology & Metabolism 96.10 (2011): 3007-3019.
  • Blask, David E. "Melatonin, sleep disturbance and cancer risk." Sleep medicine reviews 13.4 (2009): 257-264.
  • Davis, Scott, Dana K. Mirick, and Richard G. Stevens. "Night shift work, light at night, and risk of breast cancer." Journal of the national cancer institute 93.20 (2001): 1557-1562.
  • Garavello, Werner, et al. "Family history and the risk of oral and pharyngeal cancer." International journal of cancer 122.8 (2008): 1827-1831.
  • Hafe, Pedro, et al. "Visceral fat accumulation as a risk factor for prostate cancer." Obesity research 12.12 (2004): 1930-1935.
  • La Vecchia, Carlo, et al. "Diabetes mellitus and colorectal cancer risk." Cancer Epidemiology Biomarkers & Prevention 6.12 (1997): 1007-1010.
  • Morgentaler, Abraham. "Testosterone and prostate cancer: an historical perspective on a modern myth." european urology 50.5 (2006): 935-939.
  • Raynaud, Jean-Pierre. "Prostate cancer risk in testosterone-treated men." The Journal of steroid biochemistry and molecular biology 102.1 (2006): 261-266.
  • Roddam, Andrew W., et al. "Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies." Journal of the National Cancer Institute 100.3 (2008): 170-183.
  • Slattery, Martha L., and Richard A. Kerber. "A comprehensive evaluation of family history and breast cancer risk: the Utah Population Database." Jama 270.13 (1993): 1563-1568.
  • Slattery, Martha L., and Richard A. Kerber. "Family history of cancer and colon cancer risk: the Utah Population Database." Journal of the National Cancer Institute 86.21 (1994): 1618-1626.
  • Schapira, David V., et al. "Visceral obesity and breast cancer risk." Cancer 74.2 (1994): 632-639.
  • Shores, Molly M., et al. "Low serum testosterone and mortality in male veterans." Archives of internal medicine 166.15 (2006): 1660-1665.
  • Stattin, Pär, et al. "High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study." International journal of cancer 108.3 (2004): 418-424.
  • Steinberg, G. D., Carter, B. S., Beaty, T. H., Childs, B. and Walsh, P. C. (1990), Family history and the risk of prostate cancer. Prostate, 17: 337–347. doi: 10.1002/pros.2990170409 
  • Tsai, Henry K., et al. "Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality." Journal of the National Cancer Institute 99.20 (2007): 1516-1524. 
  • Ujpál, Márta, et al. "Diabetes and Oral Tumors in Hungary Epidemiological correlations." Diabetes care 27.3 (2004): 770-774.
  • Wallace, Euan M., et al. "Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study." The Journal of Clinical Endocrinology & Metabolism 82.9 (1997): 3111-3115.
  • Whitehead, E., et al. "The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male." Cancer 49.3 (1982): 418-422.