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Int Neurourol J > Volume 23(2); 2019 > Article
Cho: Treatment of Prostate Disease and Cognitive Problems
Benign prostatic hyperplasia (BPH) is one of the most common diseases in older men, affecting more than 70% of men over 70 years of age, and prostate cancer (PC) is the most common cancer in men in the United Kingdom and United States.
Clinicians use α1-adrenergic antagonists to manage lower urinary tract symptoms (LUTS) associated with BPH in older men. These drugs are often the first choice of treatment because they are effective, well tolerated, and reasonably priced. Additionally, androgen deprivation therapy (ADT) is a mainstay of PC treatment and has been shown in randomized trials to improve overall survival when used with radiation for intermediate- and high-risk localized disease, as well as locally advanced and node-positive disease [1].
Recently, some reports have suggested that these medications, which are widely used to treat BPH and PC, may adversely affect patients’ cognitive function.
Duan et al. [2] utilized Medicare claims data from 2006 to 2012 to conduct a cohort study among men aged ≥65 years who had been diagnosed with BPH. Their analysis showed that compared with the no-BPH-medication cohort, the tamsulosin cohort showed a significantly increased risk of dementia, with 31.3 vs. 25.9 cases/1,000 person-years (hazard ratio, 1.17; 95% confidence interval, 1.14–1.21) [3].
Unsurprisingly, counterarguments have been made against this study. Several studies have shown that tamsulosin has a limited ability to pass through the blood-brain barrier. Therefore, some have argued that it remains unclear how a drug with minimal penetration into the brain could promote the occurrence of dementia [4].
Adverse effects of ADT include decreases in bone mineral density, metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance. Some epidemiological studies have shown ADT to be linked with an increased risk of diabetes and cardiovascular disease [1]. Studies have shown discordant results regarding the precise impact of ADT on cognition.
Green et al. [5] randomized 82 men to a luteinizing hormonereleasing hormone agonist, cyproterone acetate, or observation. They found that half the men assigned to therapy had a clinically significant decline in one or more cognitive tests at 6 months compared with none of the men in the observation group. However, these results were not confirmed in the largest prospective study of this issue, which was conducted by Alibhai et al. [6]. They enrolled 241 men with PC treated with ADT, PC and no ADT, or no PC. After adjusting for age and education, the study found no consistent effect of ADT on cognitive function.
In the present issue of the International Neurourology Journal (INJ), Shin et al. [7] report that long-term surgical and chemical castration causes memory function to deteriorate through down-regulation of the protein kinase A (PKA)/cyclic adenosine monophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and c-Raf/mitogenactivated protein kinases-extracellular signal–regulated kinases (MEK)/extracellular signal–regulated kinases (ERK) pathway in the hippocampus. The hippocampus is a target of androgen action, and testosterone improves hippocampal neurogenesis through an androgen-dependent mechanism. Down-regulation of the PKA/CREB/BDNF and c-Raf/MEK/ERK pathways may result in decreased neurogenesis, and this result may provide an important clue regarding the cognitive decline associated with androgen deprivation.
In another study published in this issue of INJ, Yamatoto et al. [8] show the possibility that α1-adrenergic antagonists may exert an effect on the spinal cord level beyond the bladder, prostate, and urethra. They investigated naftopidil, an α1-adrenergic antagonist that has 3 times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype, and found that with anesthesia, micturition intervals were moderately shortened by emotional stress and clearly improved by naftopidil. Therefore, naftopidil appears to act at the spinal level, in addition to its other effects.
Given the high prevalence of BPH, LUTS, and cognitive impairment among elderly men, any potential impact of α1-adrenergic antagonists on cognitive function is a clinically relevant health issue. Although ADT can improve survival for men in certain settings, ADT also has a variety of potential harms to PC patients. Therefore, we should continue to investigate the effects of these drugs on the central nervous system, including the spinal cord, in addition to their effects on the target organ.

NOTES

Conflict of Interest
No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Nguyen PL, Alibhai SM, Basaria S, D’Amico AV, Kantoff PW, Keating NL, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015;67:825-36. PMID: 25097095
crossref pmid
2. Duan Y, Grady JJ, Albertsen PC, Helen Wu Z. Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia. Pharmacoepidemiol Drug Saf 2018;27:340-8. PMID: 29316005
crossref pmid
3. Frankel JK, Duan Y, Albertsen PC. Is tamsulosin linked to dementia in the elderly? Curr Urol Rep 2018;19:69. PMID: 29971698
crossref pmid pdf
4. Madersbacher S, Michel MC. Re: Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia. Eur Urol 2018;74:522-3. PMID: 30057132
crossref pmid
5. Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 2002;90:427-32. PMID: 12175403
crossref pmid
6. Alibhai SM, Breunis H, Timilshina N, Marzouk S, Stewart D, Tannock I, et al. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol 2010;28:5030-7. PMID: 21041708
crossref pmid
7. Shin MS, Kim TW, Park SS, Ko IG, Kim CJ, Kim M, et al. Long-term surgical and chemical castration deteriorates memory function through downregulation of PKA/CREB/BDNF and c-Raf/MEK/ERK pathways in hippocampus. Int Neurourol J 2019;23:116-24. crossref
8. Hattori T, Sugaya K, Nishijima S, Kadekawa K, Ueda T, Yamamoto H. Emotional stress facilitates micturition reflex: possible inhibition by an α1-adrenoceptor blocker in the conscious and anesthetized state. Int Neurourol J 2019;23:100-8. crossref
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