Terra Sigillata

If you read nothing else: Men with prostate cancer should avoid any dietary supplement containing testosterone (or anything that sounds like it) or that offers claims of increased virility, sexual performance, or increased muscle mass.

ResearchBlogging.orgConsumption of a herbal/hormone dietary supplement has been linked to two cases of aggressive prostate cancer as reported in a paper in the 15 January issue of Clinical Cancer Research (abstract free; full paper paywalled) . The observations and follow-up studies were conducted by urologists at the University of Texas Southwestern Medical School and Baylor College of Medicine. (h/t PharmGirl, MD)

These two cases are disturbing: in case #1, a 67-year-old white male presented with “a very large, asymmetric, bilaterally nodular prostate” upon digital rectal examination with metastasis to both the lung and bone. From the paper:

The patient’s history was unusual. The patient mentioned that he began taking a HHDS product (brand name not mentioned due to legal reasons) purchased via the Internet 10 months before the onset of his symptoms. He sought to develop stronger muscles and enhanced sexual performance. He took two capsules daily for 6 months, as recommended by the manufacturer. Initially, he gained 10 pounds in muscle mass and attained a higher than average energy level.


Case #2 was even more disturbing: a 51-year-old African-American man presented with “a bilaterally hard and enlarged prostate. His previous screening results were normal based on a digital rectal examination and serum T-PSA [total prostate-specific antigen] levels of 1.5 ng/mL 4 years prior, 2.3 ng/mL 2 years prior, and 2.1 ng/mL 1 year prior,” suggesting that he was free of prostate cancer a year before.

Combined androgen blockade (i.e., Zoladex® and Casodex®, respectively) resulted in a decrease in his T-PSA to a nadir of 1.3 ng/mL 3 months after start of hormone therapy. However, his T-PSA subsequently increased to 4.6 ng/mL at 10 months, 7.0 ng/mL at 12 months, and 23.7 ng/mL at 15 months. His bony symptoms worsened, and he underwent palliative radiotherapy. The patient was alive with widely metastatic disease at last follow-up. [emphasis mine]

Yes, the man’s serum T-PSA exploded while he was taking the two-drug combination to completely block, or ablate, tumor promoting effects of androgens made in the body (one drug (Zoladex) prevents the signal from the pituitary that signals the testes to make testosterone while the other (Casodex) directly blocks the testosterone at the androgen receptor). However, a medical oncologist with whom I consulted tells me that such a rapid evolution of androgen-resistance is not that uncommon, particularly in African-American men who often present with more aggressive forms of prostate cancer.

Nevertheless, the patient mentioned that he began taking the same HHDS product as the first patient described above, ~11 months before his diagnostic visit. He purchased the HHDS product over the internet after reading an advertisement in a fitness journal. Initially, he gained ~20 pounds in muscle mass but started rapidly losing weight after 3 months. He stopped taking the HHDS product after his diagnosis.

So what is this product and what’s in it? The authors stated that they did not name the product for fear of legal action – not sure if it was the researchers or the journal that made the call – but based on the ingredients listed below, I can say with 95% certainty that the product is a supplement called Teston-6.

The ingredients listed on the label of the HHDS product were as follows: 60 mg of a proprietary blend of six testosterone precursors (androstenediones and androstenediols), 100 mg chrysin, and 100 mg elk velvet antler per serving. Hormone analysis for total testosterone (Chiron Corp. Diagnostic) revealed that the HHDS contained testosterone and estradiol. Dehydroepiandrosterone levels were below the assay detection limits.

Capillary electrophoresis confirmed the presence of chrysin and elk velvet antler. Chrysin is a flavonoid found in some plants, including the geranium-like plants called Pelargonium. Chrysin is a popular nutritional supplement among male body builders and other athletes because of its aromatase-inhibitory action blocking metabolism of androstenedione and testosterone to estrogens. Elk antler velvet is marketed as an alternative medicine remedy for disorders such as impotence in men and infertility in women. Despite its popularity, a recent placebo-controlled, randomized clinical trial revealed that elk velvet antler supplementation did not enhance men’s athletic performance or change hormonal response during stress.

Interestingly, a placebo-controlled study published in the Canadian Veterinary Journal did show that elk velvet antler extract given for 60 days reduced measures of osteoarthritis in arthritic dogs (not sure if the researchers had to obtain IACUC approval for both dogs and elk – the harvesting of elk velvet is not without trauma to the elk/wapiti), with that study actually requiring IACUC approval).

But I digress. The authors then performed a series of in vitro experiments whose results were quite disturbing. The HHDS product not only promoted the concentration-dependent growth of androgen-dependent prostate cancer cells in culture, but it also promoted the growth of prostate cancer cells no longer dependent on the androgen receptor for proliferation.

So while the testosterone and other androgens in the supplement obviously would promote growth of androgen-dependent prostate cancer cells, there must be one or more other components in the product that are general stimulators of cancer cell growth (the authors did not test the supplement against carcinoma lines derived from organs other than the prostate gland.) This observation makes the use of this supplement even more disturbing.

Other in vitro experiments revealed that the HHDS supplement antagonizes the growth inhibitory effect of the anti-androgen bicalutamide (the generic name of the prescription drug, Casodex®) and causes the rapid development of bicalutamide resistance of androgen-dependent prostate cancer cells in culture.

Of course, the work does not necessarily establish causality between the HHDS and prostate cancer development or growth promotion. We also don’t know if the concentrations of the supplement used in cell culture are even achievable in patients taking the supplement. However, the results are pretty concerning and, as with any case reports, worthy of follow-up. In fact, there may be a silver lining in the fact that the supplement stimulates a growth pathway that bypasses the androgen receptor: blockade of such a pathway might result in the development of a new drug for prostate cancer.

I have one bone to pick with either the researchers or the journal in not identifying the supplement in question, particularly because bodybuilders and others may still have some of this product in their homes despite the fact it is no longer marketed:

Based on clinical data and the cell culture experiments, we filed an adverse event report with the Food Drug Administration. After acquiring an affidavit from both patients, a Food Drug Administration field officer collected their medical records as well as the HHDS. The Food Drug Administration issued a warning letter “Labeling/Promotional Claims False and Misleading/New Drug/Misbranded” leading to the removal of this HHDS from the market by the manufacturer.

Looking at some discussion threads on the web, it is clear that men want to know the supplement’s identity. As I said earlier, the composition of the product leads me to believe it is Teston-6, one of several anti-aging supplements cited by the testimony of former US senator and chairman of the Senate Special Committee on Aging John Breaux (D-LA) in 2001. You likely have not heard of the proceedings of this hearing because it took place the day before the 11 Sept 2001 terrorist attacks. Another reason that leads me to believe the product is Teston-6 is because an internet search does not list anyone who is still selling it.

Misrepresentation of the story
Just an aside here: when discussing potential benefits of herbal medicines or alternative medical practices, we decry the misuse of case reports, anecdotes, or other personal testimonials (“the plural of ‘anecdote’ is not ‘data’”) as evidence of causality. So, we have to be a little careful with this paper, although it has far more meat than a typical compilation of two cases reports: the timing of the appearance of aggressive prostate cancer, especially in case #2, the progression of disease through an androgen antagonist, and the promotion of prostate cancer cell growth in vitro by the supplement, collectively make a reasonable case that the supplement was at least involved in promoting the severity of the prostate cancer in both patients.

However, the title of the Reuters report misrepresents the study: “Natural” supplements caused cancer in 2 men: study. In no way did the authors claim causation. The Consumerist is also guilty of misrepresentation: Hormone-Filled Dietary Supplement Caused Cancer In Two Men, Say Doctors. No, the doctors did not say that.

In contrast, the original press release for the story from UT-Southwestern (shown here from EurekAlert!) responsibly promotes the significance of the work by their researchers, Hormonal dietary supplements might promote prostate cancer progression. Hence, the overinterpretation of the study was not driven by the sensationalism of the press release; rather, these two aforementioned media outlets sensationalized the press releases and the authors, in all likelihood, did not read the entire original Clinical Cancer Research paper whose PDF I’m sure was provided in the embargoed form of the press release (we bloggers had to wait until the paper came out and then find a colleague or library that subscribed to the journal).

In fact, the title of the original paper is, “Herbal/Hormonal Dietary Supplement Possibly Associated with Prostate Cancer Progression.” [emphasis mine]

I’m certainly not defending the manufacturer of this supplement, especially since the probability of causation is quite high (for increasing prostate cancer progression but not for causing the prostate cancer in the first place.) What I am saying is that the current regulation of the dietary supplement industry already allows debacles like this to occur so we needn’t misrepresent adverse events to point out these problems. Just as we admonish supplement advocates to properly represent their claims based on evidence we as bloggers and journalists should also correctly represent reports on adverse supplement effects.

There are plenty of these stories out there for the picking without overblowing the conclusions.


Shariat, S.F., Lamb, D.J., Iyengar, R.G., Roehrborn, C.G., Slawin, K.M. (2008). Herbal/Hormonal Dietary Supplement Possibly Associated with Prostate Cancer Progression. Clinical Cancer Research, 14(2), 607-611. DOI: 10.1158/1078-0432.CCR-07-1576

Comments

  1. #1 milkshake
    January 28, 2008

    The problem is that many natural remedies are not that effective at safe doses. To get some effect (even as the supplements are not supposed to trat anything) the unscrupulous manufacturers would either secretly ramp up the dosage or would lace the “natural supplement” with a synthetic active drug substance – so the supplemen turns into unregulated drug. There were numerous cases of natural herbal remedies laced with Viagra or with statins. Dietary supplement containing selenium contained 1 000 more selenium than given on label – patients feeling “lack of energy” were recommended an intensive course until diarrhoea developed – which it did, together with discoloration of skin, teeth and nails and with liver damage – symptom of chronic selenium poisoning.

    I was once taking John Worts extract capsules “for mood elevation” – using the recommended dosage – and within few days I ended up with a very nasty case of eye sensitivity because of the phototoxicity of the extract. (There were no warnings on the bottle).

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