Testosterone Replacement Therapy in Prostate Cancer Patients
Testosterone replacement therapy can be considered in carefully selected hypogonadal men with a history of definitively treated prostate cancer, as current evidence does not support the historical contraindication, though rigorous monitoring is mandatory. 1, 2
Evidence Against Historical Contraindication
The traditional prohibition against testosterone therapy in prostate cancer patients lacks robust scientific foundation. Despite decades of research, there is no compelling evidence that testosterone has a causative role in prostate cancer. 3 The original assertion by Huggins that testosterone caused "enhanced growth" of prostate cancer was based on only a single patient, and arguments supporting this concern lack scientific basis. 4
Key evidence challenging the contraindication:
- Prospective studies of testosterone replacement therapy revealed only 5 cases of prostate cancer among 461 men (1.1%) followed for 6-36 months, a prevalence rate similar to the general population. 3
- Studies using stored frozen plasma samples failed to show differences in testosterone levels between men who developed prostate cancer 7-25 years later and those who did not. 3, 5
- High endogenous androgen levels do not increase the risk of prostate cancer diagnosis. 2
The Saturation Model
The androgen receptor has finite binding capacity, explaining why prostate cancer becomes androgen-indifferent at higher testosterone concentrations. 6 This saturation model accounts for why:
- Prostate cancer is exquisitely sensitive to testosterone changes at low (castrate) concentrations but loses sensitivity at higher levels. 6
- Serum testosterone appears unrelated to prostate cancer risk in the general population. 6
- Worrisome features like high Gleason score, extracapsular disease, and biochemical recurrence have been associated with low, not high, testosterone levels. 6
Safety in Treated Prostate Cancer
After Radical Prostatectomy
Testosterone therapy appears safe in hypogonadal men after radical prostatectomy with low recurrence rates. In a review of 103 hypogonadal men treated with testosterone after prostatectomy (including 26 with high-risk cancer), only 4 recurrences were observed over median 27.5 months follow-up, compared to 8 recurrences in 49 non-hypogonadal reference patients. 7
After Radiation Therapy
Available literature provides evidence for safe application of testosterone therapy in patients previously treated with either radical prostatectomy or radiotherapy. 1 In 6 uncontrolled studies totaling 111 men treated after radical prostatectomy, external beam radiation, or brachytherapy, only 2 (1.8%) biochemical recurrences were observed. 6
Mandatory Monitoring Protocol
Before initiating testosterone therapy, men with abnormal digital rectal examination or elevated PSA must have documented negative prostate biopsy results. 3 The American College of Physicians recommends:
Baseline Assessment
- Digital rectal examination 5, 8
- PSA levels (for patients >40 years) 5, 8
- Complete blood count to monitor for erythrocytosis 5, 8
- Liver function tests 5, 8
Follow-up Schedule
PSA Monitoring Thresholds for Urologic Referral
A lower threshold for biopsy is prudent in hypogonadal men, especially during the first year of treatment. 3 Urologic referral for possible biopsy is recommended for:
- PSA increase >1.0 ng/mL during first 6 months of treatment 3
- PSA increase >0.4 ng/mL per year thereafter 3
- For PSA increases of 0.7-0.9 ng/mL, repeat PSA in 3-6 months and perform biopsy if any further increase 3
Critical Caveats
Occult Cancer Risk
The underlying prevalence of occult prostate cancer in hypogonadal men is substantial (14% in one study), even with normal PSA and digital rectal examination. 3 This underscores the importance of vigilant monitoring.
Informed Consent Required
Patients must be informed about inadequate evidence regarding the risk-benefit ratio of testosterone therapy in cancer patients. 5, 8 The decision involves weighing potential benefits (improved erectile function, quality of life) against theoretical risks. 5, 1
Contraindication in Active/Metastatic Disease
While testosterone therapy may be considered in definitively treated localized disease, it remains contraindicated in men with active metastatic prostate cancer, where androgen deprivation remains standard treatment. 3
Need for Rigorous Surveillance
Given the retrospective nature of existing studies, testosterone therapy in men with history of prostate cancer should be performed with vigorous surveillance protocols. 7 Adequately designed randomized controlled trials are necessary to confirm long-term safety and efficacy. 1