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These abdominal CT scans of a man with prostate cancer show that injections of testosterone reduced the size of metastatic tumors (red circles).

These abdominal CT scans of a man with prostate cancer show that injections of testosterone reduced the size of metastatic tumors (red circles).

Michael T. Schweizer et al., Science Translational Medicine (2015)

Cancer paradox: Testosterone injections combat lethal prostate tumors

Testosterone may be the key to manliness, but it also stokes the growth of prostate cancer cells. So injections of the hormone might sound like the last thing a man with this type of cancer needs. But a new study shows that the shots can slow the progression of untreatable prostate tumors in some patients.

Researchers have known since the 1940s that slashing the levels of testosterone and other male sex hormones can rein in prostate tumors. Today, a common treatment for prostate cancers that have spread to other parts of the body is chemical castration, drugs that cut the body’s production of testosterone and related hormones. But the cancer cells usually adapt to the low hormone levels and resume growing. For example, they sometimes crank out more of the receptor molecules stimulated by testosterone or switch to a version of the receptor that doesn’t need testosterone to prompt growth. Although researchers have devised new treatments to counteract this resistance, such as drugs that block the testosterone receptor, tumors often quickly develop resistance to them as well.

Studies of cancer cells in a dish and tumors in animals have revealed a paradox about so-called castration-resistant prostate cancer. Cancer cells that prosper when testosterone is scarce often die when exposed to high levels of the hormone. Experiments suggest that the extra hormone disrupts DNA duplication and leads to DNA fractures, which can be fatal for a cell. This paradoxical relationship means that testosterone doses could be beneficial against resistant tumors.

Medical oncologist Michael Schweizer, now at the University of Washington, Seattle, and colleagues from the Johns Hopkins University School of Medicine in Baltimore, Maryland, tested this strategy in 16 men whose prostate cancers had become resistant to chemical castration. Most of their tumors had spread, or metastasized. In the study, the men continued to receive chemical castration therapy, but every 28 days the researchers also injected them with testosterone. Each shot spiked blood testosterone levels well above normal, but they gradually declined until they were close to the level produced by chemical castration. The rationale for these oscillations, Schweizer says, is that “you don’t allow prostate cancer cells to get accustomed to one testosterone environment.” The hormone peaks will kill cancer cells that have adapted to low testosterone, whereas the valleys will stifle cells that require testosterone to grow.

To gauge the subjects’ progress, the researchers measured the amounts of prostate-specific antigen (PSA) in the blood, an indicator of prostate cancer growth. Two patients left the study after the first round of treatment because of side effects. In seven of the remaining subjects, PSA levels rose during the first three rounds of treatment, suggesting that they weren’t benefiting from the injections. But PSA levels dipped in seven others, a sign that their tumors could be shrinking. “The fact that half of the guys who got through three cycles [of treatment] showed a response is encouraging,” Schweizer says.

He and colleagues performed CT scans on 10 patients to check the size of their metastases, or tumor colonies spawned by the original growth. In four patients, the metastases had shrunk, and in one patient they had disappeared, the team reports online today in Science Translational Medicine. All five men were in the group that showed PSA declines.

Over time, however, the advantages of testosterone injections waned. PSA levels began to rise after about 7 months, suggesting renewed growth by the tumors. But even a short-term response could extend the lives of patients, because prostate cancer that is resistant to chemical castration is typically incurable, Schweizer notes. Although a few previous studies attempted to gauge the effects on prostate cancer of boosting testosterone levels, they didn’t provide the large doses of hormone necessary to kill resistant cancer cells, he says. So the new work “is a first step toward finding out who will benefit from this treatment.”

For the patients who remained in the study, side effects of the treatment included nausea and hair loss, and two subjects developed blood clots in their lungs. Of the two people who dropped out of the trial early on, one fell ill with pneumonia and died from sepsis, a body-wide inflammation that often results from infections. That’s not a typical consequence of testosterone therapy, Schweizer says, so the researchers think it was caused by a chemotherapy drug that the patients were also taking during part of the study.

Some researchers and doctors have worried that testosterone treatment might speed tumor growth, notes Charles Ryan, a cancer endocrinology researcher and physician at the University of California, San Francisco, who wasn’t involved in the work. But the study shows that “there’s potentially a substantial number of patients for whom this treatment is not harmful but is possibly beneficial.” However, he’s not ready to change how he treats prostate cancer patients until researchers perform further studies that confirm the effects of testosterone and clarify the treatment’s risks.

“They have intriguing clinical data,” says medical oncologist and prostate cancer researcher Christopher Logothetis of the University of Texas MD Anderson Cancer Center in Houston, who also wasn’t connected to the study. But he was disappointed that the team didn’t test biopsy samples from the subjects to determine how testosterone was influencing the tumors. That analysis is essential so that researchers can figure out how to predict which patients will benefit from the treatment and which might be harmed, he says.

Two other studies of testosterone therapy in patients with castration-resistant prostate cancer have begun, Schweizer notes, so researchers may soon have a better idea of whether the treatment is superior to current approaches.