Dispelling the myth of testosterone treatment and prostate cancer
Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. Debruyne FM, Behre HM, Roehrborn CG, et al. BJU Int. 2017;119(2):216-224.
Fear of prostate cancer remains one of the major concerns with testosterone therapy among doctors, and reason to deny suffering hypogonadal men testosterone treatment.1,2 This fear persists despite mounting research over the past decade that has clearly refuted the belief that testosterone therapy increased risk of prostate cancer among men in the general population.3-5 Aside prostate cancer, benign prostatic hyperplasia (BPH) with its associated lower urinary tract symptoms (LUTS) are also common concerns with testosterone therapy.6
In this editorial we summarize and comment on the results of the Registry of Hypogonadism in Men (RHYME) study; a large, multi-national prospective registry of men with testosterone deficiency, which was designed and powered specifically to assess prostate cancer outcomes in hypogonadal men receiving testosterone therapy compared with untreated hypogonadal men or general population estimates.7
BPH, LUTS and prostate cancer have long been considered major risks associated with testosterone therapy, but accumulating research shows these fears are unfounded.
The RHYME study showed that testosterone therapy does not increase prostate cancer incidence or BPH/LUTS progression compared to matched untreated men.
There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score in testosterone treated men compared to untreated men.
Testosterone therapy may improve voiding symptoms.
Testosterone therapy has no clinically significant adverse impact on prostate cancer incidence among men regardless of administration method.
What is known
Development of BPH, LUTS and prostate cancer have long been considered major risks associated with testosterone therapy.6 However, recent studies raise serious doubts about the role of testosterone therapy in BPH/LUTS and prostate cancer.
The Testosterone Trials, a large, National Institutes of Health-funded, randomised trial of transdermal testosterone compared with placebo in 800 symptomatic hypogonadal men aged >65 years found no evidence of BPH progression or increased prostate cancer incidence over 12 months of treatment.8 Specifically, the International Prostate Symptom Score (IPSS), which is used to identify symptoms of benign prostatic hyperplasia, did not differ significantly between the two groups.8
An analysis of three independent registry studies including 1,023 symptomatic hypogonadal men (baselines age 41-58 years) with total testosterone ≤12.1 nmol/L (350 ng/dL), found that testosterone therapy with long-acting injections injections of testosterone in intervals of 12 weeks (following an initial interval of 6 weeks) for up to 17 years (median 5 years) resulted in a prostate cancer incidence of 1.08%.9 This is lower than that seen in the general male population; The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality reported a prostate cancer incidence of 7.35% among 38,345 US men aged 55-74 years who were followed for 7 years.10 The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a prostate cancer incidence of 9.6% among 72,891 men aged 50-74 years who were followed for 11 years.11
Systematic reviews of published studies have also concluded that testosterone therapy does not worsen BPH progression / lower urinary tract symptoms or prostate volume 12,13, and does not increase incidence of prostate cancer.14 However, study design flaws, such as lack of untreated controls or independent adjudication of clinical outcomes, inadequate sample sizes, and short treatment durations, are key weaknesses in previously published studies.
What this study adds
The Registry of Hypogonadism in Men (RHYME) is a large, multi-national prospective registry of men with testosterone deficiency, which was designed and powered specifically to assess prostate cancer outcomes in men receiving testosterone therapy compared to untreated men with testosterone deficiency or general population estimates.
The primary aim was to examine prospectively the association between testosterone therapy and prostate health outcomes, including prostate cancer incidence and BPH progression in hypogonadal men naive to testosterone therapy, who are diagnosed and treated according to current standard-of-care guidelines.
Of 999 men with diagnosed testosterone deficiency, 750 (75%) were started on testosterone therapy. Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer. PSA and testosterone levels were measured via local and central laboratory assays, and LUTS severity was assessed via the International Prostate Symptom Score (IPSS).
Testosterone levels increased from 8.3 (239 ng/dL) to 15.4 nmol/L (444 ng/dL) in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. The proportion of positive biopsies was nearly identical in men on testosterone therapy (37.5%) compared to non-treated men (37.0%). There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score. Lower IPSS irritative sub-scale scores were reported in testosterone treated men compared to untreated men.
It was concluded that testosterone therapy does not increase prostate cancer incidence or BPH/LUTS progression compared to matched untreated men.7 Prostate cancer incidence rates in RHYME were similar to rates reported in large population studies and with findings from other single country registries. PSA levels were minimally affected and slight improvements in voiding symptoms were seen in men on testosterone therapy.7
The RHYME study clearly confirms findings from previous studies showing that testosterone therapy does not increase risk for adverse prostate outcomes. A recent study showed that 1 year of testosterone therapy with testosterone injections in hypogonadal men (age range 42-70 years) – which raised testosterone levels from 6.2 nmol/L (178 ng/dL) to 17.2 nmol/L (496 ng/dL) - did not affect PSA levels, prostate volume and maximal urinary flow rate.15
It should be noted that the achieved level of 17.2 nmol/L is the trough level, i.e. the testosterone level at its lowest point right before the next injection. The peak levels were not measured, but are likely >30 nmol/L (865 ng/dL) in most patients during the second week after each injection. The lack of change in PSA levels despite a large elevation in testosterone levels can be explained by the saturation model, which postulates that within the normal range of testosterone levels, prostate cells are saturated and unresponsive to further increases in testosterone concentration. We covered this in-depth in a previous editorial “Testosterone and Prostate Cancer - a paradigm shift”.
New trials indicate that severe LUTS may not be absolute contraindications to testosterone therapy.16 Multiple RCTs all show that testosterone replacement therapy in patients with LUTS does not worsen LUTS symptoms – measured by the validated International Prostate Symptom Score (IPSS) questionnaire – compared to placebo.17-22 Even in men with severe LUTS, no differences in IPSS were seen in men receiving testosterone replacement therapy vs. placebo.22 Notably, there was a small improvement in IPSS scores in the testosterone-treated group.22 In a registry study, testosterone therapy was interrupted due to reimbursement issues after more than 5 years of treatment. During treatment, there was a steady improvement of IPSS, supported by objective findings such as reductions in residual voiding volume and bladder wall thickness. Soon after treatment intermission, all three parameters worsened significantly and started improving again after resumption of testosterone therapy.23
In the RHYME study, testosterone prescriptions were mostly for topical gels (68%) or injectables (31%), with only 2% receiving orally administered. The lack of adverse prostate events concurs with a previous meta-analysis which concluded that testosterone therapy has no clinically significant adverse impact on prostate cancer incidence among men regardless of administration method.14
In line with the growing body of evidence supporting the prostate safety of testosterone therapy, all current major guidelines state that BPH/LUTS or low-grade prostate cancer are not absolute contraindications to testosterone therapy:
The 2015 Canadian clinical practice guideline recommends that men with testosterone deficiency receive testosterone therapy even if they have mild-to-moderate symptoms due BPH or localized prostate cancer and no evidence of active disease.24
The International Society for Sexual Medicine’s Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men 25 highlights that a series of case studies have not shown signs of recurrence among men who have received testosterone therapy after definitive treatment for localized prostate cancer 26,27 or cancer progression in men with low-grade prostate cancer on active surveillance.28
The 2016 EAU hypogonadism guidelines state that testosterone therapy does not result in changes in prostate histology, and does not increase the risk of prostate cancer.29
It is important to inform men about what to expect from testosterone therapy, both in terms of risks and benefits. When it comes to risks, as outlined in this article, fear of BPH/LUTS and prostate cancer is an unfounded reason to be denied testosterone therapy. The only safety issue with testosterone is an elevation in hematocrit (blood thickening). This being said, PSA levels (and hematocrit, of course) should be checked regularly during testosterone treatment, and sudden large spikes should prompt referral to a urologist.