Common hormone therapy to treat prostate cancer may increase dementia risk in men

A common hormone therapy to treat prostate cancer may double a man's risk of dementia, regardless of his age, Penn Medicine researchers reported in a study published online today in JAMA Oncology.

Last year, researchers discovered a dramatic association between Alzheimer's disease and androgen deprivation therapy (ADT), a mainstay of treatment for prostate cancer since the 1940s currently used in over a half million men in the United States. This new study suggests a broader neurocognitive risk associated with the testosterone-lowering therapy.

While the findings do not prove that ADT increases the risk of dementia, the analysis comparing the medical records of almost 9,500 prostate cancer patients who received ADT vs. those who did not strongly supports that possibility.

"This is not an academic question anymore; this is really a clinical question that needs to be answered," said lead author Kevin T. Nead, MD, MPhil, a resident in the department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania, and a fellow at Penn's Leonard Davis Institute of Health Economics. "We have two papers here showing very similar outcomes and magnitude of risk, which I think supports the case for this to be studied prospectively."

Androgens (male hormones) normally play a key role in stimulating prostate cell growth. Thus, therapies that suppress androgen production or activity are often used in treating prostate tumors.

Drastically reducing androgen activity can have adverse side-effects, however. Studies have found associations between low testosterone levels and obesity, diabetes, high blood pressure, and heart disease, which are also known risk factors for dementia. Research in recent years also has linked ADT and low testosterone to cognitive deficits, and has shown that men with Alzheimer's tend to have lower testosterone levels, compared to men of the same age who don't have the disease.

However, it is currently unknown if ADT may contribute to the risk of dementia more broadly.

Researchers, including senior author Nigam Shah, MBBS, PhD, an associate professor of biomedical informatics research at Stanford, and co-author Samuel Swisher-McClure, MD, MSHP, an assistant professor of Radiation Oncology at Penn Medicine, used a novel and sophisticated "text-processing" method to analyze electronic medical records from patients treated at an academic medical center from 1994 to 2013, with a median follow-up of 3.4 years. The team identified 9,277 men with prostate cancer with a mean age of 66.9 years, including 1,826 men who received ADT.

The team showed that the ADT group, compared to the control group, had significantly more cases of dementia in the years following the initiation of ADT. The absolute increased risk of developing dementia was 4.4 percent at five years: 7.9 percent among those who received ADT vs 3.5 percent in those who did not, which is more than double the risk. The results were statistically significant.

The analyses also suggested a "dose-response effect." Patients who had been receiving ADT for at least 12 months had the greatest risk of dementia, they found.

There was also no evidence of an interaction between use of ADT and age. The risk was doubled in both age groups. The probability of developing dementia at five years was 13.7 percent in men over 70 who had ADT vs. 6.6 percent in men over 70 who did not. For men younger than 70, it was 2.3 percent in those who had the therapy vs. one percent for those who did not.

There are several plausible mechanisms that may explain the association between ADT and dementia. There is some evidence that testosterone has a general protective effect on brain cells, so that lowering testosterone would leave the brain less able to resist the processes leading to dementia and Alzheimer's.

"As the population of older, long-term cancer survivors continues to rise, the health issues that cancer therapies can leave in their wake will become increasingly important," Nead said. "Further studies are needed to investigate the association between this therapy and dementias, given the significant patient and health system impacts if there are higher rates among the large group of patients undergoing ADT today."