How testosterone therapy use in men with prostate cancer has evolved

Once widely avoided, testosterone replacement in the setting of prostate cancer has become common practice, according to Wayne J.G. Hellstrom,

Until the past decade or so, says Wayne J.G. Helstrom, MD, urologists were afraid of giving testosterone to men with any kind of prostate cancer for fear of “fueling the fire.”

MD, professor of urology and chief of andrology at Tulane University School of Medicine, in New Orleans, Louisiana.

“About 20 years ago, when I gave a course at the American Urological Association [AUA] and would ask if anybody in the audience would give testosterone to a man who had prostate cancer, 3 of maybe 300 to 400 urologists would put up their hands. Now, probably 75% to 80% of urologists will give testosterone to men in these circumstances,” he observed. Until the past decade or so, he added, urologists were afraid of giving testosterone to men with any kind of prostate cancer for fear of “fueling the fire.”

Authors Huggins and Hodgkins laid the foundation for those fears in the 1940s, when they discovered that androgenetic hormones and prostate cancer were linked. Charles Brenton Huggins, who received the Nobel Prize for his work, demonstrated that if you shut down a man’s hormones you can control advanced prostate cancer, explained to Arthur L. Burnett II, MD, professor of urology at Johns Hopkins University, in Baltimore, Maryland, and author of the new book The Manhood Rx: Every Man’s Guide to Improving Sexual Health and Overall Wellness.

Based on current studies and anecdotal evidence, many of today’s urologists think it’s relatively safe to administer testosterone replacement in hypogonadal men on active surveillance or in those who have been treated with prostatectomy or cryosurgery. But these men should be closely monitored, they stress.

What the guidelines say

Guideline recommendations, however, don’t fully reflect reality. The authors of an editorial comment published earlier this year in the International Brazilian Journal of Urology found: “Last guidelines’ revisions show some changes on CaP [prostate cancer] as a definitive contraindication for TRT [testosterone replacement therapy]. The Endocrine Society has the strictest guidelines, advising against T in patients with an unevaluated prostate nodule, PSA >4ng/mL, or PSA >3ng/mL in high-risk patients (i.e., African Americans or first-degree relative with CaP). Only the AUA and ISSM [International Society for Sexual Medicine] recommend offering T on a case-by-case basis for all patients with CaP. Patients treated for localized CaP with no evidence of active disease (measurable PSA, abnormal digital rectal examination findings, evidence of bone or visceral metastases) are candidates for replacement under the Canadian Medical Association Journal, European Association of Urology (EUA), and British Society for Sexual Medicine guidelines (BSSM).”¹

Mohit Khera, MD, says, "There are no randomized placebo-controlled trials giving men testosterone therapy after prostate cancer treatments. However, initial studies have not demonstrated any increased risk of biochemical recurrence.”

The AUA released its guidelines in 2018, making a strong recommendation that clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer, according to Mohit Khera, MD, professor of urology at Baylor College of Medicine, in Houston, Texas.

“However, the guidelines go on to state that 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,” he said. “This was based on expert opinion. There are no randomized placebo-controlled trials giving men testosterone therapy after prostate cancer treatments. However, initial studies have not demonstrated any increased risk of biochemical recurrence.”

Weighing the options, one patient at a time

Men with symptomatic hypogonadism can experience symptom relief, including increased muscle mass, improved mood and cognition, and enhanced sexual health from testosterone replacement. “A significant number of men as they age are more likely to have prostate cancer, but they’re also more likely to have symptomatic hypogonadism and treatment may be warranted for these guys,” noted Hellstrom, who coauthored a paper on the topic published in Androgens: Clinical Research and Therapeutics in December 2021.²

According to Khera, the need for testosterone might be greater among prostate cancer patients. “Specifically for men with a history of prostate cancer, testosterone therapy can improve recovery of erectile function following…treatment. Testosterone plays a key role in overall erectile function.”

Although every case is different, Hellstrom said he no longer worries about starting or continuing testosterone replacement in certain patients. “As far as patients who have localized prostate cancer on surveillance and those men who have had local therapy, which may be radical prostatectomy, radiation, or cryotherapy, there is really no good evidence that men are worse off if they are hypogonadal and treated appropriately,” he pointed out. “It’s important that those men who are treated recognize that they need to be followed closely, which involves testosterone [level monitoring], PSA [prostate-specific antigen], and digital rectal exams every 3 to 6 months during treatment.”

Arthur L. Burnett II, MD, MBA, says “In a man who gets the diagnosis and has high-grade disease, the PSA [level] is rapidly going up and on top of that he says he gets a so-so benefit from the testosterone, you’d say then let’s withdraw the testosterone.”

For Burnett, things get worrisome when prostate cancer is progressing or there is metastatic disease: “If the PSA [level] is rapidly increasing, you know that prostate cancer is increasing in the body and that would increase my hesitancy about testosterone replacement.” Treating men with metastatic prostate cancer is highly controversial, the fear being that hormone replacement will increase the risk that the cancer will grow, Hellstrom said, but added that this is being put to the test by investigators studying intermittent high-dose androgen therapy in men with metastatic prostate cancer and seeing that “in a significant number of these men, the actual prostate cancer and the PSA levels regress.”

Should urologists stop testosterone replacement when men are first diagnosed with prostate cancer? Not necessarily, but for Khera there is an exception, and that is “the patient who is going on to receive radiation therapy and will require androgen deprivation therapy [ADT]. In these patients, we stop testosterone in preparation to start ADT.”

In most cases of early disease, these physicians think it’s safe to keep men with no evidence of metastases on testosterone. “I would keep him on it with the understanding that he has close follow-up,” Hellstrom said.

According to Khera, urologists should make the decision to continue therapy on a case-by-case basis, depending on Gleason score, tumor grade and stage, and their anxiety and tolerance levels.

“If it’s pretty low-threat prostate cancer and a man says I’d rather jump off a cliff than stop my testosterone, then I might say, ‘I want you to hear all the risks, but I can’t oppose you using it,’” Burnett added, noting that in every case, including new diagnoses, it’s important to factor in the benefit a man gets from taking testosterone. “In a man who gets the diagnosis and has high-grade disease, the PSA [level] is rapidly going up and on top of that he says he gets a so-so benefit from the testosterone, you’d say then let’s withdraw the testosterone.”

In fact, irrespective of PSA level change, if a patient with prostate cancer on testosterone replacement isn’t receiving adequate symptomatic relief, urologists should encourage him to stop therapy and look at what else might be causing the symptoms, including psychological or relationship factors, Burnett advised.

Is one formulation better than another?

It is all testosterone, but the delivery systems make urologists question whether there is a difference when administered to prostate cancer patients. “One therapy might have less side effects, might be easier to administer, or may have less adversity to being administered. Daily administered topical therapy, you can always just stop it. But if you put a testosterone pellet in somebody, that’s there for 3 to 6 months. Pellets are better for a person who doesn’t want to deal with the administration, but is it better when somebody may show a PSA change?” Burnett wondered. “Better depends on how you define it.”

Some regulatory bodies believe that injection therapy, which causes serum testosterone to peak at higher than optimal levels, might be worse than constant levels for patients with prostate cancer. But that’s anecdotal, according to Hellstrom, who explained thatPSA levels may go up marginally but in most cases don’t change with testosterone replacement. “That’s something you would follow very carefully. If they were to rise, that’s where a urologist would know to image a patient and do proper biopsies.”

A change in PSA typically occurs in men who have low starting testosterone levels (below 250 ng/dL), with an average rise of about 0.3 ng/mL, according to Khera.

“We are recognizing that testosterone therapy can be beneficial when correctly administered in prostate cancer patients,” Burnett said. “However, a lot of this is anecdotal, and some is a bit of the Wild West regarding the safety of who can and cannot be treated with it, considering where the literature is right now,”

The good news is that investigators are beginning to conduct the necessary randomized controlled trials, including researchers from Johns Hopkins and Brigham and Women’s Hospital, in Boston, Massachusetts, to assess the potential benefits and risks of testosterone replacement in men who have been treated for prostate cancer.³

“We’re trying to make a statement that may afford the urologists out there the necessary literature support, so if they put somebody on therapy, they can really counsel them,” Burnett said.

References

1. Javaroni V. Editorial comment: testosterone replacement therapy (TRT) and prostate cancer: an updated systematic review with a focus on previous or active localized prostate cancer. Int Braz J Urol. 2022;48(1):188-195. doi:10.1590/S1677-5538.IBJU.2022.01.08

2. Polchert M, Voznesensky I, Soubra A, Hellstrom WJG. Updated review of testosterone replacement therapy in the setting of prostate cancer. Androgens: Clinical Research and Therapeutics. 2021;2(1):36-45. doi:10.1089/andro.2020.0013

3. Valderrábano RJ, Pencina K, Storer TW, et al. Testosterone replacement in prostate cancer survivors with testosterone deficiency: study protocol of a randomized controlled trial. Andrology. 2023;11(1):93-102. doi:10.1111/andr.13299