In a recent study posted to the Research Square* preprint server, researchers conducted a meta-analysis after a systematic review of existing literature to understand the association between Androgen Deprivation Therapy (ADT) and the risk of dementia, vascular dementia, Alzheimer’s disease, and Parkinson’s disease.
Study: Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis. Image Credit: LightField Studios/Shutterstock.com
*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
Androgens play an important role in regulating the growth of not only prostatic tissue, but also in the proliferation of tumor cells, and ADT is widely used in the treatment of prostate cancer.
Prostate cancer is the most prevalent form of cancer in men, and ADT is often used as adjuvant therapy along with radiotherapy for patients with localized, locally advanced, or metastatic prostate cancer, as well as for those having undergone prostatectomy for node-positive disease.
ADT involves surgical androgen deprivation through an orchiectomy, or the use of gonadotropin-releasing hormone (GnRH) agonists or antiandrogens.
Although ADT is known to significantly improve the prognosis of prostate cancer patients, it results in a range of side effects and morbidity, including cardiovascular diseases, metabolic syndrome, sexual dysfunction, osteoporosis, and a decline in cognitive abilities.
Androgens are involved in various essential mechanisms in the neuronal microenvironment, including the degradation of β-amyloid, maintenance of synaptic density, and improving neuronal plasticity.
However, while the link between ADT and cognitive disorders such as dementia has long been suspected, epidemiological studies have reported mixed results.
About the study
In the present study, the researchers conducted a review of the studies examining the risk of dementia, vascular dementia, Alzheimer’s disease, and Parkinson’s disease among prostate cancer patients currently undergoing ADT.
Only those studies that provided a time-dependent and confounder-adjusted analysis in the form of hazard ratios of the risk of vascular dementia, all-type dementia, Parkinson’s disease, Alzheimer’s disease, and depression among prostate cancer patients undergoing ADT were included in the review.
The hazard ratios of vascular dementia, all-type dementia, depression, and Alzheimer’s dementia were the primary and secondary endpoints. Additional sub-stratification of the data was also conducted based on patient age, duration of the ADT, and the type of ADT that was used, which included bilateral orchiectomy, antiandrogens, or GnRH agonists.
Disease stage and the distribution of patient populations were also used for further subgroup analyses to account for heterogeneity.
Results
The findings indicated that the hazard ratios for dementia, depression, Alzheimer’s disease, and Parkinson’s disease were significantly higher for prostate cancer patients receiving ADT as compared to those not receiving ADT.
When the correlations between ADT and the risk of Alzheimer’s disease or dementia were stratified according to the use of bilateral orchiectomy, antiandrogens, or GnRH agonists for ADT, the results reported a significantly high risk of dementia associated with all three forms of ADT.
However, for Alzheimer’s disease, the risk was higher for bilateral orchiectomy and antiandrogens. Furthermore, the risk of dementia increased with the duration of ADT, while the risk of Alzheimer’s disease was high irrespective of the duration of ADT.
Furthermore, while the risk of dementia was found to be significantly higher when the initiation of ADT was after the age of 65 years, the risk of Alzheimer’s disease was found to be high irrespective of the age of initiation of ADT.
Furthermore, the subgroup analysis based on geography involving continental regions reported that the risk of dementia associated with ADT was high only in cohorts from America, while the risk of Alzheimer’s dementia linked to ADT was higher in the Asian and American cohorts.
Of the 28 studies included in the meta-analysis, three studies included non-cancer cohorts as controls. These studies reported that the risk of dementia was not significantly different between prostate cancer patients not undergoing ADT, and the matched controls in the non-cancer cohorts.
These findings add further credibility to the conclusion that ADT was the driver and not a confounder of the increased risk of neurodegenerative and cognitive disorders observed in these studies.
The results are also supported by various other studies and meta-analyses reporting an increased risk of dementia linked to low levels or reduced bioavailability of testosterone in men.
Conclusions
Overall, the findings indicated that androgen deprivation therapy, which is commonly used as adjuvant therapy in prostate cancer patients, is associated with a significant increase in the risk of neurodegenerative and cognitive diseases such as vascular and all-cause dementia, Alzheimer’s disease, Parkinson’s disease, and depression.
*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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