Men with low cholesterol levels have a decreased risk of high-grade prostate cancer, a recently published study suggests.

The study, which included 5,586 men aged 55 years and older randomized to the placebo arm of the Prostate Cancer Prevention Trial (PCPT), showed that men whose cholesterol levels were below 200 mg/dL had a 59% decreased risk of Gleason 8 to 10 prostate cancer compared with men who had higher cholesterol levels, researchers reported in Cancer Epidemiology, Biomarkers & Prevention (2009;18:2807–2813). Clinicians diagnosed prostate cancer in 1,251 men (22%).

The investigators, led by Elizabeth A. Platz, ScD, MPH, of Johns Hopkins Bloomberg School of  Public Health in Baltimore, found no association between cholesterol levels and prostate cancer overall.

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“Our findings add to the literature supporting a role for cholesterol in the etiology of prostate cancer with a worse prognosis,” the authors wrote.

The PCPT, which started in 1993, investigated whether finasteride could prevent prostate cancer. Researchers randomized subjects to receive 5 mg/day of finasteride or placebo for seven years. The study showed that finasteride treatment was associated with a 25% decreased incidence of prostate cancer.

In contrast to their findings in the placebo arm of the trial, Dr. Platz and her collaborators observed no association between serum cholesterol and high-grade prostate cancer in the finasteride arm. The researchers said the pattern they observed in the placebo arm, in theory, could be explained by a lower sensitivity for detecting high-grade prostate cancer in the men with low rather than high cholesterol, “but this is not the expectation.”

Men with low cholesterol, the group explained, on average have a lower prostate volume. Thus a greater proportion of the total prostate could be sampled by needle biopsy, increasing the sensitivity of detecting high-grade tumors. Another explanation, they noted, is that finasteride prevented the same subset of high-grade cancers that low cholesterol would have prevented. It also is possible that the accuracy in detecting high-grade cancers differed in men with low cholesterol in the placebo arm compared with the finasteride arm.

A prostate cancer researcher not involved with the new study, Stephen J. Freedland, MD, of the Duke Prostate Center at Duke University Medical Center in Durham, N.C., said the study by Dr. Platz’s team is consistent with previous research and “provides some of the strongest data to date” linking high cholesterol with an increased risk of high-grade prostate cancer.

Dr. Freedland said he has started to mention this association to men with high cholesterol when counseling them about whether to go for PSA testing. “I say to patients, ‘There are increasing data to suggest that high cholesterol may increase your risk of aggressive prostate cancer.’”

As for whether a man should be placed on a statin to reduce his risk of aggressive prostate cancer, Dr. Freedland observed, “If he has high cholesterol, he should probably be on a statin anyway.” It is unknown whether statin treatment would further reduce the risk in men with low cholesterol, he said.

Previous studies suggest that statin use may protect against advanced prostate cancer. For example, a study published in the Journal of the National Cancer Institute (2006;98:1819-1825) showed that statin use was associated with a 43% decreased risk of advanced prostate cancer and a 65% decreased risk of fatal or metastatic prostate cancer.

Recently, researchers reported on a study involving 1,351 prostate cancer patients who underwent radical prostatectomy (504 who used statins and 847 who did not). Preoperative PSA levels, tumor volume, and percentage of cancer in the surgical specimen were significantly lower in the statin users, who overall had a proportionately lower rate of adverse tumor pathology features, including a significantly reduced risk of positive surgical margins, researchers reported in BJU International (2009; published online ahead of print).

Dr. Freedland—whose research has focused on risk factors for prostate cancer and its recurrence following treatment, as well as on prostate cancer chemoprevention—said it is biologically plausible for cholesterol to be involved in the pathogenesis of high-grade prostate cancer.

Cholesterol is the precursor for testosterone, which promotes prostate tumor growth, Dr. Freedland said. Hypothetically, high cholesterol concentrations could mean greater testosterone production, he said. Evidence is mounting that high-grade, castration-resistant tumors can make their own testosterone from cholesterol, he noted.

Cholesterol also may directly stimulate tumor growth, he explained. In addition, all new cells need cholesterol as part of their membranes.

“Thus, lower cholesterol means it is harder for the cells to replicate,” he said. “Given that high-grade tumors grow faster, this could explain why low cholesterol only reduced the risk of high-grade disease. All of these mechanisms suggest that it is indeed plausible that high cholesterol could promote more aggressive cancers.”