Date Published: June 22, 2018
Publisher: Public Library of Science
Author(s): Thomas J. Walsh, Molly M. Shores, Chloe A. Krakauer, Christopher W. Forsberg, Alexandra E. Fox, Kathryn P. Moore, Anna Korpak, Susan R. Heckbert, Steven B. Zeliadt, Chloe E. Kinsey, Mary Lou Thompson, Nicholas L. Smith, Alvin M. Matsumoto, Aamir Ahmad.
Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP.
Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively.
Of the 147,593 men included, 58,617 were treated with testosterone. 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, 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). No association between cumulative testosterone dose or formulation and CaP was observed.
Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.
Serum testosterone declines with age, such that 20–40% of men over 40 years old have low testosterone levels[1, 2] with 2–6% having symptoms of androgen deficiency and clinical hypogonadism.[3–5] 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.[7, 8] When initiated, testosterone treatment is often short-term, usually for an average of 16 months or less[9–12]. Little is known about the safety of testosterone use in this clinical context. An increase in prostate specific antigen (PSA) within the first 12 months of initiating testosterone treatment[13, 14], combined with the association between testosterone treatment and increases in prostate size, raises concerns about the possible increase in prostate cancer risk.[15–18] Testosterone treatment could increase the near-term risk of prostate cancer by stimulating an occult tumor or it may impact risk over a longer period of time. Randomized trials that have been conducted to date have been underpowered to detect risk for prostate cancer.[19–22] Meta-analyses of these testosterone treatment trials have not found increased risk of prostate cancer but have identified an increased risk for prostate biopsy.
We identified 301,003 men aged 40 to 89 with low testosterone flagged by the testing laboratory and with complete lab data. After a priori exclusions were applied, 147,593 (49%) men remained in the low-testosterone analysis cohort. During follow-up, 56,833 men initiated testosterone treatment (S1 Fig).
In analyses adjusted for time-varying medical comorbidities, repeat testosterone testing, and intensity of PSA monitoring, and that followed men for a median of 3.0 years, we observed that in men with low testosterone levels and normal PSA levels at baseline, testosterone treatment was not associated with increased incidence of aggressive or any prostate cancer compared with untreated men. Among men who initiated treatment, we found no evidence of increased aggressive or any prostate cancer risk with increasing cumulative dose of testosterone treatment, and when our analysis was limited to men who were treated only with intramuscular or topical (transdermal) testosterone.
Among men with low testosterone and normal PSA levels who were followed for a median of 3 years, compared with untreated men, men treated with testosterone were not at increased risk of incident aggressive or any prostate cancer. The longer term clinical risks and benefits of testosterone treatment can only be definitively addressed by large, long-term randomized controlled trials.