For decades the medical community accepted the fact that testosterone replacement therapy (TRT) should never be prescribed for aging men due to the increased risk of prostate cancer.
This was especially true for men that were diagnosed with the dreaded disease. It was considered by many urologists that treating men suffering from prostate cancer with testosterone would be “like throwing gasoline on a raging bonfire.”
However, this long-held view has been challenged. A recent study produced evidence that testosterone replacement therapy (TRT) significantly improved outcomes for some men who underwent robot-assisted radical prostatectomy (RARP).
The finding is the conclusion of the study of 824 patients who underwent RARP for the primary treatment of prostate cancer. A subset of patients (n = 152, 18%) who had reduced preoperative levels of free testosterone was given TRT for postoperative recovery of sexual ability.
As an unexpected finding to the researchers, the results showed that this study group of patients had many fewer biochemical recurrences within a year of surgery. Also, TRT use was associated with longer time to recurrence and delayed disease progression compared with traditional treatment, reported Maxwell Towe, BS, a clinical research fellow at the University of California (UC), Irvine.
The findings refute entirely the rigid belief, dating to the 1940s, that states: "Thou shalt not give testosterone to men with prostate cancer."
The concern has been that testosterone will promote the growth of prostate cancer cells. As a result, typical treatment was designed to lower testosterone levels with "chemical castration" using androgen deprivation therapy (ADT).
"It's very hard to overturn guidelines and black box warnings on drugs, but I think this research is important for doing just that. We need to expand the growing body of evidence that testosterone replacement is safe and possibly beneficial for these patients," Towe said in an interview with Medscape Medical News.
Asked to comment, Francesco Montorsi, MD, director of the urology unit at San Raffaele Hospital in Milan, Italy, who was not involved in the study, said these surprising conclusions "emphasize the importance of checking testosterone levels as a part of the management of patients with sexual disorders following radical prostatectomy.”
"Obviously, selection of the right patients is vital, but if confirmed, this may have immediate benefits on quality of life," Montorsi told Medscape Medical News. "The possibility of reducing mortality would be an unexpected bonus."
The new data were presented here at the European Association of Urology (EAU) 2019 Congress. In an interview conducted before the meeting, senior author Thomas Ahlering, MD, professor and vice chair of urology at UC Irvine, explained the rationale for the study to Medscape Medical News.
"The whole thing actually started because, of the men that I was seeing, enough of them were not having recovery of sexual function. I did the same operation — why were these guys not doing as well? That's what prompted me to start measuring total and free testosterone back in 2009 on everybody," he said.
Ahlering stressed that free testosterone is the bioactive form of the hormone. He and his colleagues found that a low level of free testosterone is a separate risk factor for high-grade prostate cancer.
"We saw this really clear situation where, as the testosterone levels continued to drop, the grade — grade group in particular — started to go up, so the lower your testosterone, the more aggressive your cancer was," he said
The beginning of the “testosterone causes prostate cancer” myth
Concerns that giving testosterone to men with prostate cancer is like pouring gasoline on a raging fire date back to the work of Charles B. Huggins, MD, a pioneer of hormonal therapy for prostate cancer and co-winner of the 1941 Nobel prize for physiology or medicine.
However, recently Ahlering and his team, and other independent investigators, uncovered evidence that suggests that for some men, particularly those who have low testosterone levels at the time of surgery and who have low-risk disease, TRT may be both safe and effective, because it promotes muscle mass, improves lipid profiles, and increases libido and sexual performance."This seems to be a win-win," Ahlering said.
The Study Details
The study consisted of 824 patients who underwent RARP as the primary treatment of prostate cancer.
For all patients, testosterone and sex hormone binding globulin (SHBG) levels were measured before the operation; free testosterone levels were calculated likely.
For almost one-fifth of these men (n = 152,18%), preoperative levels of free testosterone were low. These patients started a regimen of TRT to speed up postoperative recovery of sexual function. Patients stayed on TRT throughout follow-up or until the time of biochemical recurrence.
The patients who received TRT were proportionately compared to 419 control patients from the same study by pathologic Gleason grade group and stage.
After a median follow-up of 3.1 years, TRT was linked with a 53% relative reduction in risk for biochemical recurrence, which Ahlering stated was "a big surprise."In addition, in a secondary analysis of time to biochemical recurrence, TRT prolonged the time to recurrence by a median of 1.5 years (P = .005).
In a variable analysis that considered pathologic grade, stage, preoperative prostate-specific antigen (PSA) level, and free testosterone level, the investigators concluded that TRT was an independent predictor of reduced risk for biochemical recurrence (odds ratio, 0.54; P =.049).
"Our hope is to get this to a randomized clinical trial so that we can efficiently test this hypothesis that testosterone replacement therapy will help these men who have prostate cancer," Towe told Medscape Medical News.
In another study also presented at EAU 2019, Towe and colleagues determined that patients with free testosterone levels in the lowest quartile, 4.42 ng/dL, had a higher percentage of Gleason grade group 5 disease (15.6%) than patients in the highest quartile, 6.96 ng/dL (6.2%, P = .002).In a multivariate analysis that adjusted for age and PSA level, the lower free testosterone level was a significant predictor of a high-risk score (9–10).
A urologic surgeon not involved in the study told Medscape Medical News that the findings are similar to those found in his patients.
"We also observed that patients with hypogonadal status have worse cancer prognosis because they have high-grade cancers, and also prospectively we showed that patients who have worse prognosis have a more biochemical recurrence," said Yann Neuzillet, MD, from the Hôpital Foch in Suresnes, France.
Neuzillet told Medscape Medical News that when his group planned a study of TRT similar to that of Ahlering's group, the monitoring committee objected on ethical grounds. The study was internally funded. Towe, Ahlering, Neuzillet, and Montorsi have disclosed no relevant financial relationships. European Association of Urology (EAU) 2019 Congress: Abstract 646. Presented March 17, 2019.e
The effects of testosterone replacement therapy on the prostate: a clinical perspective.
Overestimating the significance of these findings is hard. The complicated relationship between testosterone and prostate cancer has still not been conclusively settled. As with so many medical issues, more research is needed.
However, these results should cause a reevaluation of the "testosterone/prostate cancer" association.
Contact our clinic for a detailed discussion concerning what testosterone and growth hormone replacement therapy can do for you!
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