Does androgen deprivation therapy increase risk of dementia? – Medical News Bulletin

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Researchers investigate whether there is an association between androgen depletion therapy and dementia.

Prostate cancer is androgen sensitive, meaning this cancer grows in response to the presence of androgens. Androgens are male sex hormones such as testosterone and dihydrotestosterone.

Androgen deprivation therapy (the removal of circulating androgens) is one of the main approaches to treating prostate cancer. One way this can be achieved through the chronic administration of gonadotropin-releasing hormone (GnRH) agonists, a drug that prevents the testes from producing androgens. Estrogen therapy and orchiectomy (removal of the testes) are other approaches to androgen deprivation therapy both of which prevent the body from making the male sex hormones.

Androgen deprivation therapy on the rise

Since the development of a blood test for prostate-specific androgen, the diagnosis of prostate cancer has improved. As a result prostate cancer diagnoses have increased. This has contributed to an increase in the use of androgen deprivation therapy. Roughly half of all men with prostate cancer use androgen deprivation therapy at some stage after their diagnosis.

The increased use of these therapies means that patients are likely to start using these drugs at earlier times in the course of their disease and therefore use them for longer periods of time. This is a concern as androgen deprivation has numerous side effects such as skeletal fracture, diabetes, obesity, hypertension, heart attack, anemia, hot flashes, fatigue, enlargement/swelling breast tissue, and loss of libido. Importantly, there has been a growing concern that the depletion of androgens can affect cognitive function and increase the risk of getting dementia or Alzheimer’s disease.

What do androgens have to do with dementia?

Androgens are believed to affect different brain functions because the receptors for these proteins are present in various regions of the brain such as the prefrontal cortex, parietal lobe, and hippocampus. These parts of the brain are responsible for memory and other higher-order cognitive functions. Work in rodents showed that the removal of the testes can increase the production of β-amyloid protein, the protein associated with Alzheimer’s disease. In humans, there is some research to show that men with Alzheimer’s disease have lower levels of testosterone. However, there has yet to be any evidence presented to establish a causal link between low androgen levels and dementia in humans. This does, however, raise concerns about a therapy specifically designed to prevent the production of androgens in older men.

Androgen deprivation therapy is associated with a higher risk of dementia

In a recent US study published in JAMA Network Open, researchers wanted to know if there was an association between androgen deprivation therapy and dementia. The researchers used information gathered from the National Cancer Institute’s Surveillance, Epidemiology, and End Results-Medicare-linked database. The data found for 154 089 men diagnosed with prostate cancer was used in their analysis. The men were ages 66 years or older and had either local or advanced prostate cancer. The men were followed for an average of 8.3 years.

They divided the men into two groups, those that received androgen deprivation therapy within two years of their diagnosis and those that did not. The researchers then determined the number of men diagnosed with subsequent dementia or Alzheimer’s disease in each group. They showed that patients who received androgen deprivation therapy were more likely to be diagnosed with dementia than those that did not receive androgen deprivation therapy (21.6% vs 15.8%). They observed a similar trend in the diagnosis of Alzheimer’s disease, those treated with androgen deprivation therapy were at a slightly increased risk compared to the control group (13.1% vs 9.4%). The men receiving androgen deprivation therapy were 1.2 times more likely to be diagnosed with dementia.

This was an observational study and therefore confounding biases are always difficult to take into account. The numerous side effects induced by the therapy could account for this increased risk. Other confounding variables such as a family history of Alzheimer’s disease, smoking history, alcohol consumption, and educational level were not taken into consideration. The study did not account for the APOE ε4 gene in its participants. This is a gene associated with Alzheimer’s disease and could easily affect the data presented. Importantly, this study did not include a critical control group. The patients were not matched to healthy individuals. This is problematic as healthy participants of a similar age are already at a higher risk of being diagnosed with dementia, without this control group it is difficult to contextualize the increased risk observed in this study. While the study did show an association between androgen deprivation therapy and dementia, this does not prove that this therapy causes dementia or Alzheimer’s disease

Written by: Tarryn Bourhill MSc

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References:

Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nature Reviews Cancer 1, 34 (2001).

Harris, W. P., Mostaghel, E. A., Nelson, P. S. & Montgomery, B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nature Reviews Urology 6, 76 (2009).

Taylor, L. G., Canfield, S. E. & Du, X. L. Review of major adverse effects of androgen‐deprivation therapy in men with prostate cancer. Cancer 115, 2388-2399 (2009).

McHugh, D. J., Root, J. C., Nelson, C. J. & Morris, M. J. Androgen‐deprivation therapy, dementia, and cognitive dysfunction in men with prostate cancer: How much smoke and how much fire? Cancer 124, 1326-1334 (2018).

Martins, R. N. & Gandy, S. Prostate cancer: increased dementia risk following androgen deprivation therapy? Nature Reviews Urology 13, 188 (2016).

Nelson, C. J., Lee, J. S., Gamboa, M. C. & Roth, A. J. Cognitive effects of hormone therapy in men with prostate cancer: a review. Cancer 113, 1097-1106 (2008).

Jayadevappa, R. et al. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. JAMA Network Open 2, e196562-e196562 (2019).

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