Testosterone Replacement With A History of Prostate Cancer - 057

Before we tackle today’s topic, I’m letting you all know that I’ve decided to stop accepting paid subscriptions. This means that if you are on a monthly paid subscription plan, Substack will no longer charge your account. If you‘ve already paid in full, thank you! I sincerely appreciate those of you who chose to become paid subscribers.

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Introduction

I chose today’s topic when I researched the guidelines for testosterone replacement therapy (TRT) in men with a history of prostate cancer and was pleasantly surprised by what I found.

When I was in med school and residency, this was forbidden territory - we wouldn't even consider it. The conventional wisdom was absolute: testosterone would fuel any existing cancer cells like throwing gasoline on embers.

Now? The evidence has pushed us to rethink everything. It’s these types of fundamental shifts in medicine that consistently renew my commitment to advancing medical education

In addition, based on this emerging evidence, the 2018 American Urological Association guidelines provide cautious yet evolving recommendations, which I’ll detail later in this article.

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Testosterone replacement in men on active surveillance

Active surveillance (AS) is the standard of care for monitoring low-grade, low and intermediate-risk localized prostate cancer. The goal of AS is to monitor for possible progression while preventing or delaying therapy with inherent side effects.

Several retrospective studies have examined the safety of TRT in AS:

• Morgentaler et al. (2011): This study followed 13 men with prostate cancer on active surveillance who received TRT. The median follow-up period was approximately 30 months. Twelve men had low-risk disease, and one had intermediate-risk prostate cancer. All men had a follow-up biopsy as a part of their protocol, and no upgrading or prostate cancer progression was reported.

• Kacker et al. (2015): A retrospective study of prostate cancer progression rates in testosterone-deficient men on active surveillance. There were 28 men in the treatment arm and 96 men in the control arm who went untreated. Biopsy proven progression rates were similar between both groups over a 3-year follow-up period.

• Ory et al. (2016): A retrospective study examined eight men on active surveillance with low-volume Gleason 6 who received TRT for a median of 27 months. Six of the eight men had follow-up biopsies. None of the eight showed clinical or pathologic progression, and none moved on to definitive treatment.

• Kaplan‐Marans et al. (2024): A retrospective study of men with prostate cancer on active surveillance comparing 167 patients receiving testosterone therapy with 6658 patients not receiving testosterone. The median follow-up was 5.2 years for the testosterone group and 4.7 years for the no-testosterone group. There were 28 (17%) conversions to active treatment in the testosterone group and 1455 (22%) in the no-testosterone group. There were no prostate cancer-specific deaths in the testosterone group compared to 39 (0.6%) prostate cancer-specific deaths in the no-testosterone group.

• Applewhite et al. (2025): This recent retrospective analysis involved 43 men on active surveillance. With follow-up periods of 44.3 and 79.5 months, the study found stable PSA levels and similar progression rates compared to the general AS population.

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TRT in men previously treated for prostate cancer

In men who have undergone treatment for prostate cancer, the decision to initiate TRT for testosterone deficiency is complex.

Studies that have examined the safety of TRT in men treated for prostate cancer:

• Pastuszak et al. (2013): This retrospective study evaluated the safety of transdermal TRT in 103 hypogonadal men who had undergone radical prostatectomy for prostate cancer, comparing them with 49 non-hypogonadal men post-surgery. Over a median follow-up of 27.5 months, the testosterone-treated group experienced a modest rise in PSA. However, these PSA changes were not consistent with cancer recurrence, and the rate of biochemical recurrence was lower in the treatment group, even among those with high-risk disease.

• Kaplan et al. (2016): A literature review of multiple studies reported that TRT in men with a history of prostate cancer did not lead to higher recurrence rates or worse oncologic outcomes.

• Ory et al. 2016: A retrospective analysis of TRT-treated men observed no biochemical recurrence in 22 men treated with radical prostatectomy, although 3 of 50 (6%) treated with radiation therapy experienced biochemical recurrence. Of those, two were high-risk patients, and one was intermediate risk.

• Jones and Snyder (2023): A retrospective study of 16 men who were testosterone deficient before radical prostatectomy for organ-confined disease and resumed TRT after surgery. There was no biochemical recurrence during a median follow-up of five years.

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Limitations of these TRT studies in men with a history of prostate cancer:

While these studies are promising, it is crucial to keep in mind their limitations:

• Retrospective studies generate hypotheses; prospective randomized controlled trials would be needed to confirm the results.

• Active surveillance protocols used by different providers may vary, affecting the study groups' comparability.

• Many lacked data such as testosterone serum levels, testosterone dosage, and treatment indications.

• Lack of randomization can introduce bias and limit the studies’ viability.

• Many of the studies had small sample sizes, which can undermine the validity of the results.

In addition, the lack of robust data in these studies reflects the most recent American Urological Association and European Association of Urology guidelines reporting:

There is insufficient evidence to determine the risk-benefit ratio of testosterone therapy for men with a history of prostate cancer.

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A paradigm shift

Despite the lack of robust data to support the use of TRT in hypogonadal men with a history of prostate cancer, modern data also doesn’t suggest that TRT contributes to the development of prostate cancer. The American Urological Association guidelines go as far to say:

Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)

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The 2018 American Urologic Association guidelines offer insight and guidance for the treatment of men with a history of prostate cancer.

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Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. (Expert Opinion)

“It is the opinion of this Panel that the decision to commence testosterone therapy in men with in-situ prostate cancer on active surveillance or previously treated prostate cancer is a negotiated decision based on the perceived potential benefit of treatment weighed against the limited knowledge of potential risks.”

Post-radical prostatectomy

“Testosterone therapy can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively.”

Radiation therapy

“Available studies evaluating the safety of testosterone therapy in men treated with RT have suggested that after RT patients (with or without a history of androgen deprivation therapy) do not experience recurrence or progression of prostate cancer and experienced either a steady decline in PSA values to <0.1 ng/mL or had non-significant changes in PSA.”

Active surveillance

“There are limited data on men on active surveillance who are candidates for testosterone therapy. Available literature indicate that patients with and without high-grade prostatic intraepithelial neoplasias who were on testosterone therapy did not experience significant increases in PSA or subsequent cancer diagnosis compared to men not receiving testosterone.”

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Patient Selection

Ideal candidates for TRT are those with:

• Favorable pathology: Organ-confined disease, negative surgical margins, and undetectable PSA levels post-treatment.

• Significant symptom burden: Patients experiencing severe hypogonadal symptoms - fatigue, reduced libido, erectile dysfunction - refractory to lifestyle modifications.

• Informed decision-making: Uncertainty about long-term outcomes requires thoroughly discussing the risks, benefits, and alternative therapies between the patient and clinician.

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General guideline recommendations regarding TRT

• Recommend that a prostate-specific antigen (PSA) level should be measured in men over age 40 before beginning testosterone therapy to help exclude a prostate cancer diagnosis.

• Practitioners should use a total testosterone level cutoff of 300 ng/dL to support a diagnosis of low testosterone.

• Diagnose “low testosterone” only after measuring two total testosterone levels taken on separate occasions, both drawn in the early morning.

• A clinical diagnosis of “testosterone deficiency” can only be made with a combination of low testosterone levels and symptoms +/- signs.

• Recommends using the minimal dosing necessary to bring testosterone levels to the normal physiologic range of 450-600 ng/dL.

• If patients do not have symptom relief after reaching the testosterone level target at three to six months, they should discuss stopping TRT with the patient.

• After reaching therapeutic targets, measure total testosterone every six to twelve months.

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Conclusion

Testosterone replacement for men with a history of prostate cancer requires a careful, personalized approach based on the latest evidence.

If you're on active surveillance, the research isn't comprehensive yet, but current studies suggest TRT might not make your cancer worse. And if you've had treatment like a radical prostatectomy or radiation with good results, TRT could be an option if your doctor monitors you closely.

The American Urological Association updated its guidelines in 2018 to reflect this changing perspective. The association acknowledges that while recent data looks promising, we still lack high-quality controlled studies that would give us complete confidence.

Their recommendations make sense: carefully select appropriate patients, aim for moderate testosterone levels, and keep a close eye on PSA levels.

If you’re considering TRT and have a history of prostate cancer, having a thorough conversation with your doctor is crucial. You'll need to weigh potential benefits, such as better energy, sex drive, and mood, against the uncertainties that exist.

I hope this information helps you and your practitioner make an informed decision that aligns with your health needs and quality of life goals.

Until the next newsletter, stay healthy.

Much love,

Keith