Will "Muscle Building Supplements" Give You Testicular Germ Cell Cancer? Creatine & Protein Stand in the Pillory

The study at hand makes protein and creatine look worse than prohormones - can that be right?

Maybe you've already seen a link to this study on Facebook, maybe not: "Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts" - that's the title of a study which claims to provide convincing evidence that "MBS use is a potentially modifiable risk factor that may be associated with TGCC" (Li. 2015), a study of which I don't have to tell you that it is of observational nature, a study based on interviews with 356 cases and 513 controls and thus a study that may and certainly is skewed by false recalls and deliberate lies - I mean, who would admit to have used illegal steroids if at Yale? Some may, but others certainly won't.
That being said, reason #1 to take the results of the study with the necessary skepticism is a combination of false recall and flat-out lies / not disclosing one's complete "supplement" regimen. Moreover, the fact that the subjects were asked about a finite set of 30 different types of MBS powders or pills which certainly didn't include powerful designer steroids made it even easier for the study subjects to conceal some o the "supplements" (haha) they actually took. Against that background it's a bold claim to say that

"Considering the magnitude of the association and the observed dose-response trends, muscle-building supplements use may be an important and modifiable exposure that could have important scientific and clinical importance for preventing testicular germ cell cancer development if this association is confirmed by future studies" (Li. 2015).

That's even more true in view of the fact that lies and recall errors are one thing that hampers the reliability of the results, while a statistically significant difference in the rate of (again) reported injuries to the groin which has long been shown to increase the risk of testicular cancer (Coldman. 1982; Oliver. 1994) is another one and reason #2 to take the results of this study with appropriate skepticism.
The fact that the 95% confidence levels (95% CI: 1.11–2.46 total cancer risk, 95% CI: 1.34–3.63 cancer before 25, 95% CI: 1.39–4.74 long-term use) adds another question mark to the claim that using creatine once or regularly is going to give you germ cell cancer.

Figure 2: While both undescended testes and injuries to testes and groin can increase the risk of testicular cancer, only the latter shows a statistical significant inter-group difference between cases and controls (Li. 2015).

In conjunction with reason #3 which is the fact that there is absolutely no mechanism that would explain pro-carcinogenic effects of non-steroidal supplements in general and creatine and protein supplementation in particular (creatine has even been shown to inhibit breast cancer and general tumor growth | Miller. 1993; Juhn. 1998 and anti-tumor effects mostly in the colon, though, of whey protein have been reported among others by  Eason, 2004; Xiao, 2005 & 2006; Parodi, 2007; Attaallah, 2012; etc.), you may even call it "bad science" or "sensationalism" that that none of the several "reviews" of this study on the Internet mention the most important of all findings, which is the non-significance of the results of the TGCC subtype analysis and reason #4:

"Analyses by TGCC subtype suggested similar associations between use of MBS and the risk of seminoma and nonseminoma  (all the P-values for hierarchical coefficients tests were >0.05)."

Against that background I would be curious how the scientists were able to do an exploratory stratified analysis which found that "both creatine and proteins increased the risk of TGCC significantly (OR =2.55, 95% CI: 1.05–6.15)" (Li. 2015).

Table 1: Association Between MBS Use and the Risk of TGCC, Connecticut and Massachusetts, 2006–2010 (Li. 2015).

That sounds very odd considering the facts that (a) no associations were found for a complete analysis, that (b) there's no mention what exactly the data was stratified for and that (c) no previous epidemiological study provides the slightest hint that there may be a potentially causal association between supplement use and testicular cancer.

Speaking of causality, you are aware that the "odds ratios" from the case-control study like the one at hand provide extremely weak evidence? Evidence that cannot provide any information about cause and effect? If that's not your first visit to the SuppVersity you probably knew that already. If it's not, I believe it may be worth remembering that correlation and causation are two different pairs of shoes; or, like my friend Carl Lanore likes to explain it: Just because there are firefighters all over the place, whenever a house burns down (association), they're not the cause of the fire (causation).
References:

• Attaallah, Wafi, et al. "Whey protein versus whey protein hydrolyzate for the protection of azoxymethane and dextran sodium sulfate induced colonic tumors in rats." Pathology & Oncology Research 18.4 (2012): 817-822.
• Coldman, A. J., J. M. Elwood, and R. P. Gallagher. "Sports activities and risk of testicular cancer." British journal of cancer 46.5 (1982): 749.
• Eason, Renea R., et al. "Dietary exposure to whey proteins alters rat mammary gland proliferation, apoptosis, and gene expression during postnatal development." The Journal of nutrition 134.12 (2004): 3370-3377.
• Li, N., et al. "Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts." British journal of cancer 112.7 (2015): 1247-1250.
• Juhn, Mark S., and Mark Tarnopolsky. "Potential side effects of oral creatine supplementation: a critical review." Clinical Journal of Sport Medicine 8.4 (1998): 298-304.
• Key, Timothy J. "Nutrition, Hormones and Prostate Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition." Prostate Cancer Prevention. Springer Berlin Heidelberg, 2014. 39-46.
• Miller, Elizabeth E., Audrey E. Evans, and Mildred Cohn. "Inhibition of rate of tumor growth by creatine and cyclocreatine." Proceedings of the National Academy of Sciences 90.8 (1993): 3304-3308.
• Oliver, M. C. "Social, behaviouraland medical factors in the aetiology of testicular cancer: results from the UK study." Br. J. Cancer 70 (1994): 513-520.
• Parodi, Peter W. "A role for milk proteins in cancer prevention." Australian journal of dairy technology 53.1 (1998): 37-47.
• Schottenfeld, Davit, et al. "The epidemiology of testicular cancer in young adults." American Journal of Epidemiology 112.2 (1980): 232-246.
• Xiao, Rijin, Thomas M. Badger, and Frank A. Simmen. "Dietary exposure to soy or whey proteins alters colonic global gene expression profiles during rat colon tumorigenesis." Molecular Cancer 4.1 (2005): 1.
• Xiao, Rijin, et al. "Dietary whey protein lowers serum C-peptide concentration and duodenal SREBP-1c mRNA abundance, and reduces occurrence of duodenal tumors and colon aberrant crypt foci in azoxymethane-treated male rats." The Journal of nutritional biochemistry 17.9 (2006): 626-634.