Clinical Topics

Testosterone Therapy Not Linked to Aggressive Prostate Cancer in Veterans

by U.S. Medicine

October 5, 2018

SEATTLE—Clinicians prescribing supplemental testosterone in men with low levels always have a nagging concern about the possible link between increasing hormone levels and prostate cancer.

Now, a new veterans’ study in PLOS ONE reported that testosterone supplementation does not appear to be linked to an increased risk of aggressive prostate cancer.1

A study team lead by researchers from the VA Puget Sound Health Care System and the University of Washington, both in Seattle, came to that conclusion after examining records of nearly 150,000 veterans 40 and older with low testosterone levels who had been treated with supplements.

Urologist Tom Walsh, with patient at the UW Medicine Men’s Health Center. (Photo by Clare McLean.)

“This finding doesn’t change the guidelines for how we recommend testosterone therapy,” said lead author Thomas Walsh, MD, MS, a VA Puget Sound clinician who also is an associate professor of urology at the University of Washington School of Medicine. “Men should still have their testosterone diagnosed appropriately, with multiple readings, and be counseled about risks and benefits of treatment. But this large foundation of evidence allows us to look patients in the eye and say testosterone therapy does not appear to increase risk of prostate cancer over a moderate duration.”

Background information in the study noted that testosterone treatment of men with low testosterone is common and, although usually short-term, has raised concern regarding an increased risk of prostate cancer (CaP), leading to the investigation of the association between modest-duration testosterone treatment and incident aggressive CaP.

The retrospective inception cohort study focused on male veterans 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing. Overall, 58,617 of the participants were treated with testosterone, and 313 aggressive CaPs were diagnosed—190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49–0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48–0.69).

After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, researchers determined that testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70–1.13) or any CaP (HR 0.90; 95% CI 0.81–1.01).

Furthermore, they observed no association between cumulative testosterone dose or formulation and CaP.

“We now know that the nonaggressive variations can simply be followed over time and may not lead to significant increases in morbidity or mortality. So, for the study, we thought it was more important to identify the high risk prostate cancer associated with very high PSA or known histologically to be prone to spread,” Walsh said, emphasizing that the focus was on development of aggressive prostate cancer.

Importance of VA Data

The study benefited from VA’s closed medical and pharmacy system, he added, pointing out that using an integrated healthcare system reduced the likelihood that patients in the study received relevant care outside of the system. In addition, patients’ data sets included full medical histories, enabling researchers to better control for other serious illnesses that affected the study population’s mortality.

Finally, Walsh pointed out, most recipients of testosterone therapy received intramuscular injection, the typical delivery mechanism during the study span and also the most biologically available testosterone therapy.

“Many previous studies of testosterone delivered in topical cream or patch have shown that men never achieve a biologically therapeutic level. In our study, most men received injections and had follow-up tests that proved that their testosterone levels actually rose with the therapy,” he explained.

The study noted that, because serum testosterone declines with age, as many as 40% of men over 40 years old have low testosterone levels, with 2-6% having symptoms of androgen deficiency and clinical hypogonadism.

“Despite clinical guidelines recommending testosterone treatment only for men with symptomatic androgen deficiency and consistently low testosterone levels, testosterone therapy has been used increasingly to treat men with a single low testosterone level,” the report added. “When initiated, testosterone treatment is often short-term, usually for an average of 16 months or less. Little is known about the safety of testosterone use in this clinical context.”

Study authors pointed out that “an increase in prostate specific antigen within the first 12 months of initiating testosterone treatment combined with the association between testosterone treatment and increases in prostate size, raises concerns about the possible increase in prostate cancer risk.”

The researchers posited how that might happened, including that the hormone could potentially stimulate an occult tumor, or it might impact risk over a longer period of time. They cited meta-analyses that have not found increased risk of prostate cancer but have identified an increased risk for prostate biopsy.

All of that makes their results significant, the study authors added.

“These findings are important given the rise in testosterone treatment and concerns for its potential associated risks,” the researchers wrote. “Given the association between testosterone treatment and increase in PSA levels and prostate biopsy, information on the near term risk of prostate cancer among this group of men is important for clinical decision making. In hypogonadal men, testosterone treatment increases prostate size and PSA.”

They said it remained unclear if testosterone treatment increases “the risk for incident prostate cancer or if it alters the natural history of pre-existing organ-confined prostate cancer. Recent meta-analyses of placebo-controlled testosterone treatment studies found conflicting results on the association of testosterone treatment with prostate cancer risk.”

1. Walsh TJ, Shores MM, Krakauer CA, Forsberg CW, et. Al. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels. PLoS One. 2018 Jun 22;13(6):e0199194. doi: 10.1371/journal.pone.0199194. eCollection 2018. PubMed PMID: 29933385; PubMed Central PMCID: PMC6014638.


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