Testosterone therapy did not increase prostate cancer risk in hypogonadal men

Abraham Morgentaler, MD, FACS

The study by Haider and colleagues provides invaluable real-world confirmation that testosterone therapy does not increase the risk of developing prostate cancer. Rates of cancer in more than 1,000 treated men followed for a median of 5 years, with the longest follow-up 17 years, were lower than reported rates in large populations.

It has taken many years, and many studies, to de-fang the long-held but unfounded belief that increasing serum testosterone causes de novo prostate cancer, or causes occult prostate cancer to grow rapidly. Hopefully, this study will provide additional reassurance for clinicians that have been hesitant to treat hypogonadal men due to fears of adverse events. 

Donald L. Trump, MD, FACP

Haider and colleagues report an interesting and instructive analysis of 1,023 hypogonadal men, treated with testosterone [testosterone undecanoate (Aveed, Endo Pharmaceuticals) 1,000 mg every 12 weeks] for as long as 17 years. Patients were gathered from three separate prospective registries, two urology practices and one reproductive medicine/andrology program. Patients were described as carefully followed and adherent to medication and follow-up. PSA was monitored and biopsies were done for PSA absolute value of greater than 4 ng/mL or greater than 0.75 ng/mL rise in any 12-month period.
In these men (age range, 15 to 84 years), 92 biopsies were done and 11 were positive for prostate cancer. Based on these data, the “rate” of prostate cancer was calculated as 1.08% among the 1,023-person cohort. This rate was contrasted with rates of 7.35% in the Prostate, Lung, Colorectal and Ovarian (PLCO) trial and 9.6% in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. This led the authors to conclude, with caution, that testosterone does not increase the risk for prostate cancer in hypogonadal men.
Although this may be true and these data certainly are consistent with that hypothesis, this reviewer suggests that caution is still justified when considering such testosterone replacement. Among the two largest concerns from this analysis are that the ages of the men studied in the registries (15 to 84 years), as the authors pointed out, are quite different from the ages of men in the PLCO and ERSPC studies. In the latter two trials, entry criteria required that men be aged older than 55 years or 50 years, respectively. There is no doubt that these age differences could substantially modify “expected” rates of prostate cancer in these registries. No data are provided regarding the numbers of men in each decade of life in the registries, though mean ages were 59.53 ± 8.35, 57.37 ± 7.04 and 41 ± 12 years, respectively.
Secondly, follow-up is short. Although some men were followed for as long as 17 years in the registries, the median follow-up was 5 years. In the history of prostate cancer, this is a short time. Additionally, this analysis suffers from the unavoidable problems of any registry trial. Although individuals were considered “adherent,” given the small number of prostate cancer cases found and biopsies performed in these single-arm, essentially retrospective and relatively small series, the possibility for small frequencies of nonadherence to have large effects is real. Consequently, this reviewer would agree that this analysis provides some reassurance that testosterone replacement may be safe; it would be premature in my view to declare the answer “in.”
Considerable caution is still warranted, and careful counseling of individuals is indicated. It is clear that testosterone is the primary contributing factor to the genesis of prostate cancer in the average man. Testosterone signaling is of paramount importance — so restoring/enhancing such signaling by providing testosterone replacement in a manner that does not mirror normal testosterone secretion should be viewed with caution.