Androgen Deprivation Therapy Associated With Dementia
There has been conflicting evidence regarding the association between androgen deprivation therapy (ADT) use and development of dementia. A new large study appears to link exposure to ADT and increased incidence of dementia in men with prostate cancer.
A new study from the University of Pennsylvania, Philadelphia published this month in JAMA Network Open, found that older men with prostate cancer who received ADT were about 20 percent more likely to develop Alzheimer’s disease or dementia within eight years of their cancer diagnosis compared to men not receiving ADT. The authors reported a dose response relationship whereby those who received more ADT had a higher likelihood of developing long-term cognitive issues.
Androgen-deprivation therapy (ADT) is intended to reduce the level of the male sex hormone testosterone, which fuels the growth of prostate cancer cells. ADT alone or as part of multi-modal therapy, reduces the likelihood of cancer progression and mortality in high-risk localized, locally advanced, recurrent, or metastatic prostate cancer. Despite these benefits, is has become increasingly apparent that ADT has long-term effects on bone, sexual, and cardiovascular health that influence prostate cancer - related quality of life and functional status. The possible association between ADT exposure and cognitive dysfunction represents an additional growing concern.
Studies have been mixed as to the association of ADT and dementia, with a few small previous studies showing no link between ADT and dementia. But many of these studies had flaws such as varying inclusion criteria, no account for duration of ADT treatment, had short follow-up, or included a heterogeneous study population. Other recent better quality studies and meta-analysis, however, have demonstrated increased development of dementia with exposure to ADT [Gonzalez et al., 2015; Nead et al., 2017).
This current study confirms earlier work, in which testosterone deficiency has been associated with Alzheimer’s disease, and is important because of its large size. The researchers analysed retrospective data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare (SEER) linked database. They included data from 154,089 men in the U.S., average age 75, who were diagnosed with prostate cancer between 1996 and 2003 and who had no evidence of dementia before diagnosis or treatment. Of those, 91,759 went untreated, while 62,330 underwent some form of ADT within two years of being diagnosed. Patients were followed for an average of 8.3 years. The authors stratified patients by how many doses of ADT therapy they received in the two years after diagnosis - fewer than five, five to eight, and eight or more.
Overall, those who had exposure to ADT had 20 percent greater odds of developing dementia. Those who received four or fewer doses had a 19 percent likelihood of developing dementia, while those received five to eight doses had a 28 percent likelihood.
How ADT causes cognitive decline is not entirely clear. Decreasing testosterone levels may increase risk factors for Alzheimer disease and dementia, including loss of lean body mass, diabetes, cardiovascular disease, and depression. There may be a causative relationship between lower testosterone levels and impaired cognitive function, perhaps via impaired neuron growth and axonal regeneration or accumulation of abnormally folded β-amyloid protein. It is possible that ADT simply accelerates a process that is already underway, rather than being the cause of dementia.
The list of effective ADT agents has recently grown with the addition of androgen synthesis inhibitors and second-generation antiandrogens. Furthermore, there is increasing data to support the use of such agents earlier in the course of disease progression. The results of this large analysis do suggest that we should carefully weigh the long-term risks and benefits of exposure to ADT and stratify patients based on dementia risk prior to ADT initiation. Additionally, for those on ADT, every effort should be made to mitigate its long term negative effects and decrease the risks of dementia through nutrition, brain boosting herbs and lifestyle - see the related articles for tips on keeping your brain healthy.
