Common prostate cancer therapy disrupts brain's hippocampal memory system.
Oregon Health & Science University researchers studying how testosterone deprivation affects verbal memory found that men undergoing the prostate cancer therapy forget things faster than their healthy counterparts.
Scientists in the OHSU School of Medicine's departments of Behavioral Neuroscience and Medicine, and the OHSU Cancer Institute, in a study to be presented Sunday to the Society for Neuroscience in San Diego, found that word retention drops sharply after only two minutes among men undergoing testosterone deprivation therapy.
However, initial learning of the words, or encoding, was the same for testosterone-deprived and healthy men, according to the study titled "Androgen ablation impairs hippocampal-dependent verbal memory processes."
Men who have undergone testosterone deprivation "are able to encode these words well, and if I ask them immediately, they can recall them as easily as non-hormone-deprived men," said Joseph Bussiere, a graduate student in behavioral neuroscience and the study's lead author. "But after only two minutes, there's a marked drop-off. When you stretch the time between encoding and retrieval, that's where the problem lies."
In testosterone deprivation or "ablation," the testicles are surgically removed or medications are given to block the production of male hormones, principally testosterone, that can promote prostate cancer growth. This common treatment for prostate cancer wipes out most male hormones found in the body.
Bussiere and Jeri Janowsky, Ph.D., professor of behavioral neuroscience and neurology, OHSU School of Medicine, say the rapid drop in memory suggests the lack of testosterone affects the function of the hippocampus, a curved, elongated ridge in the brain that controls learning and memory. In fact, Janowsky said, similar deficits - the ability to encode information initially but forget it quickly - is seen in individuals with well-known cognitive disorders.
"A colleague looked at (the study results) and said, 'Wow, that looks exactly like what happens with a lesion in the hippocampus,'" Janowsky said. "When others have done studies like this on people who have hippocampal damage from early Alzheimer's disease or lesions due to strokes, this is the pattern."
The study examined 30 individuals - 14 men undergoing androgen deprivation treatment for prostate cancer and 16 healthy, age-matched men - from the Portland area. Participants were shown lists of words and, to encode them, were asked to identify whether the words were in capital or lowercase letters, which requires shallow or "perceptual" processing, or whether they represented objects that occurred in nature or were artificially made, which requires deep or "semantic" processing.
Participants were then shown another list containing words they'd just seen as well as new words and were asked whether they'd seen each word before. This test was performed at three time intervals: immediately, after two minutes and after 12 minutes.
Testosterone-deprived men can "immediately get the information in, but then the hippocampus can't consolidate it and send it off for storage," Janowsky said. "When you look at their memory, they're perfectly normal when they're immediately asked to recall something, but they can't hold or save the information as well in order to recall it over a retention interval, over a period of time. They're faster at forgetting."
These results, Bussiere and Janowsky say, point to a negative effect of testosterone deprivation in the hippocampus, which is responsible for storing information from the first few seconds on. Both the prefrontal cortex and hippocampal memory systems commonly show declines with aging and are associated with problems in attention and memory.
"But for long-term memory, the critical structure is the hippocampus. It doesn't mean the prefrontal cortex doesn't participate, but it's the hippocampus that's important for these results. After the information gets in, the hippocampus and other nearby structures are responsible for processing and storing it over minutes, to days and weeks," Janowsky said.
The next step in the research is to use brain imaging to assess the function of the hippocampus in men on testosterone deprivation therapy, which will be developed at OHSU's Advanced Imaging Research Center. One study will look at changes in blood flow in parts of the brain that are activated during the memory tests, and another will examine the effects of testosterone deprivation on structures in the brain.
"We can see during each task what parts of the brain are active and how the two brains (testosterone deprived versus normal ) differ," Bussiere said.
Janowsky, whose laboratory focuses on how cognition changes with aging, said healthy older men, on average, have about a 40 percent loss in their normal levels of testosterone as they age, from the ages of 20 or 30, to 70, but that some men in their 80s can have normal and high testosterone levels like men half their age.
"This is an important first step in an effort to fully understand how prostate cancer therapies adversely affect memory and other brain functions, and to develop therapies that do not produce such undesirable effects," said Tomasz Beer, M.D., associate professor of medicine and director of the OHSU Cancer Institute Prostate Cancer Research Program. Beer was a co-investigator in the effort
The study is one in a series of ongoing research projects funded by the National Institute on Aging that examine sex hormones, particularly testosterone and estrogen, as neuromodulators and their roles in cognitive function in aging. A study in which Janowsky and Beer collaborated found that high-dose estrogen can be used as a testosterone deprivation tool for men with prostate cancer, but that these testosterone-deprived men showed better memory performance than men undergoing traditional testosterone deprivation treatment.
Other collaborators on the study included Michelle Neiss, a senior research associate of behavioral neuroscience, and Beer.