Mark Whitacre Research Review: Prostate Health

In 2015, the Global Burden of Disease Study (a) reported that, on average, men are expected to live 5.8 years less than women. Although this is attributable to many factors (b) –such as genetics, immune system responses, and behavioral differences–, diseases like prostate cancer have an alarming impact. Being the second most common type of cancer in American men (c), it inspires us to talk about prevention. Cypress joined this conversation at a pivotal time in selenium (Se) research, and we want to share two of the most relevant gold-standard studies in the field:

 1. The Nutritional Prevention of Cancer Trial (NPC) sparked global interest in the benefits of Se. Researchers journeyed to discover if a nutritional agent, high Se yeast (SelenoExcell®), could decrease the incidence of skin cancer.

Since the initial proposal that geographic distribution of Se in the United States was inversely correlated with cancer mortality, made in 1969, several experimental and epidemiologic studies explored the potential of increasing Se status to reduce cancer risk (d). As Se compounds had shown antitumorigenic activity in animal models at higher levels that what is associated with nutritional requirements, the team designed this multicenter, randomized, double blind, placebo-controlled trial, using oral supplementation of 200 mcg of Se/day, as high selenium yeast (SelenoExcell®).

The study followed a total of 1312 subjects (18-80 years; average 63 years) with a history of skin cancer that were randomized from 1983 through 1991. The treatment lasted a mean of 4.5 years with a 6.4-year follow up, with patient examinations every 6 months.

The plasma Se levels in the population at the start of the study was 114 ng/mL, which is on the lower end of the data reported as normal in the United States. This was consistent with the Se in the area from which the group was recruited. The subjects in the Se group reached about 190 ng/mL after 6 to 9 months of supplementation.

As the National Cancer Institute (NCI) approved screening procedures and funding for long-term follow up became available, the researchers selected secondary endpoints in 1990: all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. After a trial audit and NCI approval, the blinded phase ended in January 1996.

 Although Se intervention did not protect against skin cancer, the analysis of the secondary endpoints revealed the following:


Reduction %

(compared to placebo)

P value

Total Cancer mortality



Total Cancer incidence



Prostate cancer



Colorectal cancer



Lung cancer




No signs of Se toxicity or adverse effects were found, confirming the safety of Se yeast at the chosen dose, which is within the range of dietary intake for Americans and about 3 – 4 times the RDA for this mineral. Additionally, every batch of pills was tested for mineral content to ensure Se levels.

Back then, the authors cautioned that the effects needed to be confirmed in an independent trial before making public health recommendations for this nutrient. By now, many researchers have dived into the subject to discover more benefits and mechanisms through which Se works.

The groundbreaking results of the NPC trial set the stage for worldwide investigation of the potential in this micronutrient, even leading to an FDA Qualified Health Claim for Se and cancer.

Larry C. Clark, MPH, PhD; Gerald F. Combs Jr, PhD; Bruce W. Turnbull, PhD; et al. Effects of Selenium Supplementation for Cancer Prevention in Patients with Carcinoma of the Skin. A Randomized Controlled Trial. JAMA. 1996;276(24):1957-1963. doi:10.1001/jama.1996.03540240035027

 2. As the debate over the difference in the action of high Se yeast and selenomethionine (SeMet) unfolds, researchers at Penn State University designed the first study in humans that evaluated these Se forms side by side.

In this randomized, double blind, placebo-controlled trial, 69 healthy men (23-78 years; average, 51 years) were supplemented with Se yeast (SY, 200 and 285 mcg/day – from SelenoExcell®) and SeMet (200 mcg/day) for 9 months. They focused on comparing the treatments’ effects on oxidative stress biomarkers, relevant to prostate cancer; as secondary aim, they assessed the effect on PSA and glucose levels.

Subjects returned to the clinic every 3 months for sample collection and pill refill. At 9 months, all participants were given placebo (as a “flush” period). Measurements were performed as follows: 

Outcome measures

Period tested (months)






Plasma total Se






Blood free and protein-bound glutathione (GSH)






Urinary 8-hydroxy-2´-deoxyguanosine (8-OHdG)*






Urinary 8-iso-prostaglandin-F2a (8-iso-PGF2a)**






Blood glucose and serum PSA






Se speciation in plasma






+ B= baseline

*8-OHdG – oxidative stress biomarker related to lipid peroxidation.

**8-iso-PGF2a – oxidative stress biomarker related to DNA damage. 

As expected, plasma Se increased during supplementation and decreased during the “flushing” period; no serious adverse effects were reported. GSH, glucose, and PSA did not change throughout the study. 

Analysis of the oxidative stress biomarkers revealed a decrease of 34% for 8-OHdG, and of 28% for 8-iso-PGF2a in the 285 mcg/day SY group. This dose was chosen as the equivalent to 200 mcg/day of SeMet (considering SY contains about 70% SeMet). No significant changes were observed in the other groups, supporting the development of SY as the preferred intervention agent in future studies: form makes a difference.

The largest decreases in the oxidative stress biomarkers were found in the participants with low baseline Se (≤127 mcg/L), which aligns with previous studies and highlights the importance of a personalized approach to Se supplementation.


John P. Richie Jr, Arun Das, Ana M. Calcagnotto, Raghu Sinha, et al. Comparative Effects of Two Different Forms of Selenium on Oxidative Stress Biomarkers in Healthy Men: A Randomized Clinical Trial. Cancer Prevention Research, 2014, 7(8), 1–9.


  • Wang, H., Naghavi, M., Allen, C., Barber, R. M., Bhutta, Z. A., Carter, A., ... Murray, C. J. L. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 2016, 388(10053), 1459-1544. DOI: 10.1016/S0140-6736(16)31012-1
  • Anna Oksuzyan, Knud Juel, James W. Vaupel, Kaare Christensen. Men: good health and high mortality. Sex differences in health and aging. Aging Clinical and Experimental Research, 2008, Volume 20, Issue 2, pp 91–102.
  • Clark, L. C., & Alberts, D. S. (1995). Selenium and cancer: Risk or protection? Journal of the National Cancer Institute, 87(7), 473-476. DOI: 10.1093/jnci/87.7.473


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