Higher levels of percent-free testosterone (%FT) are associated with an increased risk of high-grade prostate cancer (PCa) being found on initial prostate biopsy, researchers concluded.

Simone Albisinni, MD, of Sant’ Andrea Hospital, Second School of Medicine, “La Sapienza” University, Rome, and colleagues analyzed data from 812 white Italian men who no history of PCa and who underwent 12-core prostate biopsies. They evaluated testosterone, free testosterone, and %FT as predictors of low-grade (Gleason score of 6 or less) or high-grade (Gleason score of 7 or higher) PCa. A greater %FT level significantly predicted high-grade but not low-grade PCa.

Men in the highest tertile of %FT (above 0.23%) had a significant twofold increased risk of high-grade PCa compared with those in the first tertile (below 0.15%), Dr. Albisinni’s team reported in Urology (2012;80:162-168). Testosterone and free testosterone levels were not significantly associated with low- or high-grade PCa.

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The reason a greater %FT level might determine high-grade disease is not known, the investigators stated. It is possible that in men with elevated %FT, “the hormonal milieu (elevated free testosterone and low total testosterone) might concurrently drive overexpression of the androgen receptor (as a consequence of low total testosterone) and its increased activation secondary to elevated free testosterone penetrating into the cell,” they wrote.

In addition, testosterone can bind to extracellular membrane receptors and exert a pro-apoptotic effect. “Thus, although free testosterone stimulates the cell through the intracellular androgen receptor, low total testosterone might simultaneously result in reduction of this extracellular receptor-mediated apoptotic pathway, possibly leading to increased proliferation,” the researchers explained.

In an accompanying editorial, Sandip M. Prasad, MD, of the University of Chicago, and co-authors said the “holy grail” in PCa is to differentiate potentially lethal tumors from those unlikely to metastasize or cause death. “A key success factor would be a simple, inexpensive, readily available laboratory test, such as %FT,” they wrote, adding that Dr. Albisinni and her colleagues “provide intriguing findings in this regard.”

The editorial noted that although an association between elevated %FT and high-grade PCa was identified, it is unknown whether the relationship is causal. They pointed out: “Complex intraprostatic biology that defines the interaction between free testosterone and the aggressiveness of PCa remains poorly understood and requires further study; importantly, the findings in this study might not be applicable in other racial and ethnic groups in which the disease biology might differ.”