PROSTATE CANCER Testosterone Replacement After Definitive Prostate Cancer Treatment: Where Do We Stand?

By: Matthew J. Ziegelmann, MD, Mayo Clinic, Rochester, Minnesota; C. Scott Collins, MD, Mayo Clinic, Rochester, Minnesota | Posted on: 19 Sep 2023

Testosterone deficiency is defined by low circulating testosterone levels and the presence of attributable symptoms.1 The true incidence is unknown due to variation and controversy regarding what testosterone level defines testosterone deficiency. Until relatively recently, the prospect of offering testosterone replacement therapy (TRT) for patients with prostate cancer (PCa) was considered well outside the norm of standard practice. Early work from Huggins and Hodges showed that PCa cells are fueled by androgens, and application of testosterone to PCa cells results in cellular growth.2 This work formed the basis upon which androgen deprivation has been used to treat metastatic PCa. It also created trepidation towards the use of TRT for hypogonadal patients with a history of PCa.

Over the last 2 decades, the dogma that patients with a history of treated PCa are not candidates for TRT has been brought into question. It is now well-established that TRT does not cause PCa or PCa recurrence after local treatment.1 Morgentaler and Traish popularized the saturation model, which postulates that androgen receptors within prostate and PCa cells become saturated at levels far lower than normal circulating serum testosterone levels (around 200-250 ng/dL), and that raising exogenous testosterone levels beyond this threshold would have no further impact on cell growth.3 This model suggests that patients who are hypogonadal but not castrate can receive exogenous testosterone to raise circulating levels to a eugonadal state without risk for PCa proliferation.3

One of the earliest reports on the safety of TRT after PCa treatment came from Kaufman and Graydon in 2004.4 In their study of 7 patients who received TRT after radical prostatectomy (the majority with Gleason 6 disease), no patient experienced biochemical recurrence (BCR). Since that time, there have been multiple retrospective series published, all showing relatively low and comparable rates of BCR when comparing TRT vs observation after radical prostatectomy. Interestingly, in one of the largest retrospective series to date from Ahlering et al, BCR rates were actually significantly lower in the TRT group (7.2% compared with 12.6% in the observation/control group). The idea that TRT may be protective against PCa recurrent is certainly intriguing but warrants more dedicated research.

For the most part, similar outcomes are seen with TRT after radiation therapy.1,5 Most studies to date have included patients with only low and intermediate risk PCa. However, one study from Pastuszak and colleagues found that patients with high-risk PCa (Gleason ≥8) who underwent radiation therapy had a significantly greater risk in their PSA (mean increase from 0.10 to 0.36 ng/mL; P = .018) compared to those with intermediate and lower risk at a median follow-up of 41 months.6 Only 6/98 patients (6.1%) experienced BCR overall, and all of these patients had intermediate- or high-risk PCa. Further work is needed to characterize outcomes in patients with high-risk disease. Most patients who receive radiation therapy for intermediate- and high-risk disease also receive concurrent androgen deprivation therapy (ADT) for anywhere from 6 months to 2 years. It may be prudent to wait several months or longer after radiation and ADT before starting TRT to determine if endogenous androgen production will recover.1 Roughly 75% of men will have total testosterone levels >300 ng/dL within 2 years of stopping ADT, although only 50% return to their baseline testosterone levels.7

There is also a small body of evidence to support TRT for patients on active surveillance, now considered the treatment of choice for most patients with low-risk PCa and considered even for those with favorable intermediate-risk disease.5,8 In the largest cohort to date, Morgentaler and colleagues reported a 10% progression rate (defined as an increase in Gleason score) in men on active surveillance treated with TRT for >4 years.9

Currently, the AUA Guideline Panel for the Evaluation and Management of Testosterone Deficiency recommends that patients with a history of PCa should be counseled on the “inadequate evidence to quantify the risk-benefit ration of testosterone therapy” in men with hypogonadism. This recommendation is based on expert opinion due to the absence of high-level evidence. The expert panel from the International Consultation for Sexual Medicine Recommendations for Diagnosis and Treatment of Testosterone Deficiency states that “it may be reasonable to offer [TRT] to selective men with a history of PCa, particularly those who appear to be disease-free after definitive treatment of low-risk, localized disease.”10

There are several important considerations for TRT in patients with a history of treated PCa. First, the AUA guideline panel recommends a goal total testosterone within the middle tertile, defined as 450-700 ng/dL. This seems like a reasonable and safe target for men with treated PCa, particularly if one considers the saturation model. Second, all patients on TRT should be closely followed with routine labs obtained periodically to monitor for treatment efficacy and side effects.1 In addition to routine safety labs, we also monitor serum PSA more closely during the early time frame after starting TRT—obtaining a baseline PSA followed by repeat serum PSA at 6 weeks, 3 months, 6 months, and every 6 months thereafter. Third, short-acting formulations such as gels or injections should be considered initially. If there is a change in serum PSA, these agents can be stopped quickly. Finally, while not mandatory, it may be reasonable to consider having patients engage in a more formalized consent form prior to starting therapy to ensure appropriate documentation of your discussion regarding risks and benefits.

In summary, patients with symptomatic hypogonadism should not be deprived the opportunity for TRT. There are numerous retrospective studies suggesting that TRT can be used safely in patients with a history of definitive treatment for localized PCa. That being said, until we have more robust data, it is imperative that we engage our patients in the tried and true shared decision-making model of care.

Conflict of Interest Disclosures: The Authors have no pertinent conflicts of interest to disclose.

  1. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432.
  2. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22(4):232-240.
  3. Morgentaler A 3rd, Conners WP. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian J Androl. 2015;17(2):206-211.
  4. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172(3):920-922.
  5. Kim M, Byun SS, Hong SK. Testosterone replacement therapy in men with untreated or treated prostate cancer: do We have enough evidences?. World J Mens Health. 2021;39(4):705.
  6. Pastuszak AW, Khanna A, Badhiwala N, et al. Testosterone therapy after radiation therapy for low, intermediate and high risk prostate cancer. J Urol. 2015;194(5):1271-1276.
  7. Nascimento B, Miranda EP, Jenkins LC, et al. Testosterone recovery profiles after cessation of androgen deprivation therapy for prostate cancer. J Sex Med. 2019;16(6):872-879.
  8. Eastham JA, Boorjian SA, Kirkby E. Clinically localized prostate cancer: AUA/ASTRO guideline. J Urol. 2022;208(3):505-507.
  9. Morgentaler A, Magauran D, Neel D, et al. MP17-03 Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. J Urol. 2018;199(Issue 4S):e206.
  10. Morgentaler A, Traish A, Hackett G, et al. Diagnosis and treatment of testosterone deficiency: updated recommendations from the Lisbon 2018 international consultation for sexual medicine. Sex Med Rev. 2019;7(4):636-649.