Androgen Deprivation Therapy and its Impact on Neurological Health

Introduction
Androgen Deprivation Therapy (ADT) hinders androgen release in prostate cancer, facilitating cancer cell regression and halting disease advancement. Its application has expanded from metastatic to localized prostate cancer.¹ Prolonged ADT for androgen suppression triggers a swift drop in androgen, known as ‘Andropause’, which brings about various adverse effects based on dose and duration, including cognitive issues like dementia. ^1,2

In a recent study, researchers performed a meta-analysis following a systematic literature review. The goal was to explore the connection between Androgen Deprivation Therapy (ADT) and the potential for dementia, vascular dementia, Alzheimer’s disease, and Parkinson’s disease.¹

Significance of Androgens in Prostate Cancer
Androgens exert a crucial influence on prostatic tissue growth and tumor cell proliferation. ADT finds widespread use in prostate cancer treatment. Prostate cancer stands as the most prevalent male cancer. ADT is frequently employed with radiotherapy for localized, locally advanced, or metastatic cases and after prostatectomy for node-positive disease. ADT entails surgical androgen reduction (orchiectomy) or using gonadotropin-releasing hormone (GnRH) agonists and antiandrogens.² While significantly enhancing prostate cancer prognosis, ADT triggers various effects:

• Cardiovascular issues
• Metabolic syndrome
• Sexual challenges
• Osteoporosis
• Cognitive decline

Androgens play pivotal roles within the neuronal microenvironment, including β-amyloid degradation, synaptic density maintenance, and neuronal plasticity enhancement. Nonetheless, the suspected link between ADT and cognitive disorders, such as dementia, has yielded mixed results in epidemiological studies.^1,2

About the Study
In this study, researchers reviewed investigations that explored the potential of dementia, vascular dementia, Alzheimer’s disease, and Parkinson’s disease in prostate cancer patients receiving ADT. The review included only studies that presented time-related and confounder-adjusted analyses, specifically hazard ratios. These analyses examined the risks of vascular dementia, all-type dementia, Parkinson’s disease, Alzheimer’s disease, and depression in prostate cancer patients on ADT.¹

The main and secondary focuses were the hazard ratios concerning vascular dementia, all-type dementia, depression, and Alzheimer’s dementia. Additionally, the data was further divided by patient age, ADT duration, and type of ADT – involving bilateral orchiectomy, antiandrogens, or GnRH agonists. Subgroup analysis took into account disease stage and patient dispersion to address variations.^1,2

Study’s Emphasized Findings¹

• The investigation notably revealed significantly elevated hazard ratios for dementia, depression, Alzheimer’s disease, and Parkinson’s disease in prostate cancer patients under ADT compared to those without ADT.
• When associating ADT with Alzheimer’s disease or dementia risk, the analysis accounted for ADT methods—bilateral orchiectomy, antiandrogens, or GnRH agonists. All three ADT forms correlated with notably heightened dementia risk.
• While Alzheimer’s disease risk was notably increased with bilateral orchiectomy and antiandrogens, dementia risk escalated with prolonged ADT use. Alzheimer’s disease risk remained elevated regardless of ADT duration.
• Dementia risk was notably higher when ADT commenced after age 65. Yet, Alzheimer’s disease risk persisted regardless of initiation age.
• A geographical analysis revealed that dementia risk associated with ADT was evident in American cohorts, while the risk of Alzheimer’s disease was notable among Asian and American males.
• Among the 28 studies examined, three included non-cancer cohorts as control groups. These studies demonstrated no significant difference in dementia occurrence between prostate cancer patients without ADT and carefully matched non-cancer controls.
• These findings support the notion that ADT serves as a driving factor rather than a confounding variable in the heightened susceptibility to cognitive and neurodegenerative conditions observed in the research.
• Many studies and meta-analyses concur, indicating an increased risk of dementia linked to low levels or limited testosterone availability in men.

Considering Neurological Associations

While the potential link between ADT and these neurological conditions is intriguing, it’s important to note that the research is still evolving, and more comprehensive studies are needed to establish causality definitively. The relationship between hormone levels and neurological health is complex, and other factors, such as age, genetics, and lifestyle, could also contribute to the observed associations.^2,3

Clinical Implications
For medical professionals, these findings highlight the importance of a holistic approach when considering ADT as a treatment option for prostate cancer.¹ Physicians should consider the potential neurological risks alongside the benefits of cancer control. Patients undergoing ADT should be closely monitored for mood, cognition, and motor function changes. Regular screening and early intervention for depression and neurological symptoms may be crucial in managing potential side effects.³

Conclusion
In conclusion, the results highlighted a notable link between androgen deprivation therapy, frequently employed as adjuvant treatment for prostate cancer and a substantial rise in the likelihood of developing neurodegenerative and cognitive conditions. These include vascular and all-cause dementia, Alzheimer’s disease, Parkinson’s disease, and depression.^1,2,3

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References

1. Hinojosa-Gonzalez, D. et al. “Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis”. August 2023. DOI: 10.21203/rs.3.rs-3221041/v1. Available at: https://www.researchsquare.com/article/rs-3221041/v1
2. Jayadevappa R, Chhatre S, Malkowicz SB, Parikh RB, Guzzo T, Wein AJ. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men with Prostate Cancer. JAMA Network Open. July2019;2(7): e196562. DOI: 10.1001/jamanetworkopen.2019.6562.
3. Lee HH, Park S, Joung JY, Kim SH.   How Does Androgen Deprivation Therapy Affect Mental Health including Cognitive Dysfunction in Patients with Prostate Cancer? World Journal Men Health. October 2021;39(4):598-605. https://DOI.org/10.5534/wjmh.200092