ONLINE DRIVERS MEDIA

Dont 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? Im 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.
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 dont 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.
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, thats 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.
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 Hodgkins disease and combination chemotherapy on gonadal function in the adult male." Cancer 49.3 (1982): 418-422.

Shouldnt it be obvious that the "happy medium" must be the solution, when high protein leads to brittle bones, and low protein to frail muscle? Sure! But where is this "happy medium"?

Some of you may remember my recent Facebook post "High Protein Diet in the Firing Line. Rodent Study Says: Kidneys Are at Risk". It was based on a press release you could read on all the major science-news outlets on the Internet; a press release that will give the average reader the impression that the corresponding study by Aparicio et al. would "prove" that high protein diets will ruin your kidneys and eventually jeopardize your health (read more).

Another paper (Cao. 2014), Jose Antonio, the CEO of the ISSN and the editor of the ISSNs journal posted on Facebook yesterday, didnt get as much media attention, though.

No wonder, the message of this study is after all not in line with one of the fundamental arguments you will hear, whenever you question the allegedly necessary restriction of total protein intake to 0.8g/kg, maximally 1.2g/kg protein per kilogram body weight day in the current nutritional guidelines:

"[...S]hort-term consumption of high-protein diets does not disrupt calcium homeostasis and is not detrimental to skeletal integrity."

Thats not what you will learn at med-school and it is certainly not in line with the hysteria about protein intakes that are 2x or even 3x higher than the 0.8g protein per kilogram body weight we are supposed to consume. Apropos RDA, the subjects in the control group of the said study by Jay J Cao et al. consumed a diet that contained exactly those 0.8g/kg body weight thats supposed to be good for us. The 21 human guinea pigs in the treatment groups, on the other hand, consumed 2x and 3x more than the average dietitian would recommend and they did so for 31 days (Cao. 2014).

Figure 1: Protein intake (in g/day; left), mineral intake (in mg/day; middle)  and calculated renal acid load (in mEq; right) of 49 normal weight, healthy men (n=32) and women (n=7) who consumed normal (0.8g/day), high (1.6g/kg per day) and very high protein (2.4g/kg per day) energy restricted (40%) diets for 4 weeks (Cao 2014)

If you take a look at the PRAL values in Figure 1, you can see that math (not bio- or physiology!) tells us that this reckless practice could compromises the acid-base balance of the healthy, normal-weight subjects, whose energy restricted diets were modeled on the increasingly popular high protein weight loss diets.

Equations vs. experiments | PRAL vs. urinary calclium loss | theory vs. practive

The urinary analysis the scientists conducted does yet speak a very different language. There is, as the scientists emphasize in the discussion of the results no evidence that

Suppversity Suggested Read: "High protein diet = high protein loss" | more

"habitual consumption of dietary protein at levels above the RDA [would] significantly alter urinary calcium excretion, dietary calcium retention, or markers of bone turnover or BMD, despite increased urinary acidity. These results indicate that diets that are 2 or 3 times the RDA for protein are not detrimental to calcium homeostasis when calcium and vitamin D are consumed at recommended intake"

In that I would like to emphasis the importance of adequate calcium (min. 800mg/day) and vitamin D intakes (800-1000IU/day) and the fallacy of the word "habitual". The study at hand did not test the effects of "habitual" high protein consumption. It tested the effects of short-term (28 days) high protein consumption in a low calorie scenario, which is by definition less prone to produce adverse inflammatory and thus potentially pro-osteoporotic side effects (Mundy. 2007).

Not eating enough protein could increase bone loss, when youre dieting

In view of the fact that the evidence I am about to cite, stems from rodent model of postmenopausal bone metabolism, I deliberately used the word could in the headline of this paragraph. And still, the way in which the low protein diet  "negatively impacted bone mass and magnified the detrimental effects of vitD and/or estrogen deficiencies" (Marotte. 2013) in the pertinent study from the Buenos Aires University is particularly disturbing.
The (postmenopausal) women the scientists try to model with their ovariectomized rats (=rats whose ovaries have been removes) are after all one of the many patient groups who are advised to carefully control their protein intake to make sure that the additional acid load will not compromise their bone health even further and that in spite of the fact that there is ample evidence that the current RDA for protein is inadequate to maintain optimal health, particularly when the total energy intake is restricted and especially in populations who are susceptible to bone loss (Kerstetter. 2005; Chernoff. 2004).

Figure 2: We know for quite some time not that low protein diets decrease the absorp- tion of protein (Kerstteter. 2005). Its not certain if this is "just" a homeastatic me- chanism to stabilize the net/acid balance.

In their 2005 study, Kerstetter et al. were in fact able to show that protein intakes that are 2.6x higher than the RDA increase the effective absorption of calcium from the diet (see Figure 2).

This increase stands in contrast to the significant decrease in calcium absorption the researchers observed in the healthy young (age: 26y) women in the low protein arm (0.7g protein per kg body weight) of the study and should remind us that a reduction in protein intake is not going to stop the insidious loss of bone thats caused by the triage of low estrogen, no exercise and a diet that may be low in protein, but high in acid producing grains (Remer. 1995) and devoid of alkaline fruit and vegetables.

I could now go more into details, but I will just leave you with the notion that the "paleo diet" is, despite its high meat content, among the most kidney-, and above all bone-friendly diets we know. In fact, its fruit and vegetables content yield a net alkaline renal load, and will lead to significant improvements in urinary calcium excretion rates (Appelet. 1997; Frassetto. 2013).   

? Note: If you want more about the "Paleo connection" - let me know this (best on Facebook) and what you would be most interested in and I will address that in a future SuppVersity article.

References

• Aparicio, V. A., et al. "High-protein diets and renal status in rats." Nutrición hospitalaria: Organo oficial de la Sociedad española de nutrición parenteral y enteral 28.1 (2013): 232-237.
• Appel, Lawrence J., et al. "A clinical trial of the effects of dietary patterns on blood pressure." New England Journal of Medicine 336.16 (1997): 1117-1124. 
• Cao, Jay J., et al. "Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized controlled trial." The American journal of clinical nutrition 99.2 (2014): 400-407.
• Chernoff, Ronni. "Protein and older adults." Journal of the American College of Nutrition 23.sup6 (2004): 627S-630S. 
• Frassetto, L. A., et al. "Established dietary estimates of net acid production do not predict measured net acid excretion in patients with Type 2 diabetes on Paleolithic–Hunter–Gatherer-type diets." European journal of clinical nutrition 67.9 (2013): 899-903.
• Kerstetter, Jane E., et al. "The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women." Journal of Clinical Endocrinology & Metabolism 90.1 (2005): 26-31.
• Mundy, Gregory R. "Osteoporosis and inflammation." Nutrition reviews 65.s3 (2007): S147-S151.
• Remer, Thomas, and Friedrich Manz. "Potential renal acid load of foods and its influence on urine pH." Journal of the American Dietetic Association 95.7 (1995): 791-797.

Red (meat) breast cancer alert!

Its not the first study and I am pretty sure its not going to be the last study to link red meat and cancer, but in view of the fact that I am pretty sure that the results Maryam S Farvid and colleagues present in their latest paper in the British Journal of Medicine are going to be all over the place this week, I feel that its worth to give you an unbiased overview of the results before you are confronted with the sensational press release celebrating the newest "Harvard science" - a source people trust, one that "propagates the truth" and one that is (ab-)used by press release writers to generate the impression that each and every word they write is true.

Well the truth is that we are dealing with yet another prospective epidemiological study which does not have the power to reveal causal links between parameter (a), in this case the dietary protein sources in early adulthood and parameter (b), which is the incidence of breast cancer.
The average ignoramus will still read the headlines as "red meat" causes cancer and think of poultry, fish, eggs, legumes, and nuts as "the cure". In contrast to the red meat intake which was associated with a 22% risk increase in the 2830 documented cases of breast cancer the scientists had been collecting and following for 20 years, the a higher intake of poultry, fish, eggs, legumes, and nuts was
not just unrelated to breast cancer, in postmenopausal women, a high poultry intake was even associated with a -27% reduced breast cancer risk.

Energy intake and cancer risk expressed relative to lowest intake quintile for red meat (Farvid. 2014)

The latter observation gives rise to one of the (imho) hilarious substitute this for that equations, where the "estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Substituting poultry for red meat was even associated with 17% and 24% lower breast cancer risk in all and postmenopausal women.

Unlike the fooled readers of the press release, the researchers are obviously aware of the weaknesses of the study, in the discussion of the results, Farvid et al. point out that "potential limitations need to be considered":

• participants were predominantly white, educated US adults, they cannot determine whether our findings are generalizable to other race or ethnic groups
• dietary intake was assessed by food frequency questionnaires, some degree of measurement error is inevitably present, and thus to reduce measurement error they used the cumulative average of
  multiple measurements in a sensitivity analysis
• residual confounders are always of concern in any observational studies; although they adjusted for a wide range of potential confounders for breast cancer, they still could not rule out the possibility that other unmeasured or inadequately measured factors have confounded the true association
• they only estimated the effects of substitution of legumes, poultry, and other protein sources for red meat on risk of breast cancer, when trials on dietary modification would be ideal to support these substitutions

In addition, the scientists made multiple comparisons (different food groups and nutrients, premenopausal and postmenopausal subgroups, and subtype of tumors) in this analysis, and can thus not exclude the possibility of type I errors. But (sarcasm) this is not so much of concern, "the central finding of an association with red meat was [after all] a prior hypothesis." (Farvid. 2014) - In other words: What do you want people, weve just made sure we confirm our hypothesis.
Reference:

• Farvid, et al. "Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study." BMJ 2014;348:g3437 doi: 10.1136/bmj.g3437