Risk of dementia and Parkinson's disease in patients treated with androgen deprivation therapy using gonadotropin-releasing hormone agonist for prostate cancer: A nationwide population-based cohort study.

Myungsun Shim,Hanjong Ahn,Seong Soo Jeon,Yong Seong Lee,Cheol Young Oh,Young-Su Ju,Jin Seon Cho,Woo Jin Bang,Gianluigi Forloni

doi:10.1371/journal.pone.0244660

Abstract

Recent studies reported conflicting results on the association of androgen deprivation therapy (ADT) with dementia and Parkinson's disease in patients with prostate cancer (Pca). Therefore, this study aimed to investigate whether use of gonadotropin-releasing hormone agonist (GnRHa) increases the risk of both diseases. A nationwide population cohort study was conducted involving newly diagnosed patients with Pca %who started ADT with GnRHa (GnRHa users, n = 3,201) and control (nonusers, n = 4,123) between January 1, 2012, and December 31, 2016, using data from the National Health Insurance Service. To validate the result, a hospital cohort of patients with Pca consisting of GnRHa users (n = 205) and nonusers (n = 479) in a tertiary referral center from January 1, 2006 to December 31, 2016, were also analyzed. Traditional and propensity score-matched Cox proportional hazards models were used to estimate the effects of ADT on the risk of dementia and Parkinson's disease. In univariable analysis, risk of dementia was associated with GnRHa use in both nationwide and hospital validation cohort (hazard ratio [HR], 1.696; 95% CI, 1.425-2.019, and HR, 1.352; 95% CI, 1.089-1.987, respectively). In a nationwide cohort, ADT was not associated with dementia in both traditional and propensity score-matched multivariable analysis, whereas in a hospital validation cohort, ADT was associated with dementia only in unmatched analysis (HR, 1.203; 95% CI, 1.021-1.859) but not in propensity score-matched analysis. ADT was not associated with Parkinson's disease in either nationwide and validation cohorts. This population-based study suggests that the association between GnRHa use as ADT and increased risk of dementia or Parkinson's disease is not clear, which was also verified in a hospital validation cohort.

Highlights

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (GnRHa) has dramatically increased [1] because it has been widely used for the treatment of metastatic prostate (Pca) and loco-regional disease with high-risk features given the fact that randomized evidence supports the use of androgen deprivation therapy (ADT) in combination with external beam radiation therapy [2, 3]
The risk of cognitive impairment has been suggested in the previous study because it is known to be associated with decreased testosterone levels and the ADT effects are based on its ability of suppressing the testosterone level [8, 9]
The hospital validation cohort was composed of 205 GnRHa users and 479 nonusers as control group, and 34 (4.9%) patients developed dementia and/or Parkinson’s disease during the study period

Summary

Introduction

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (GnRHa) has dramatically increased [1] because it has been widely used for the treatment of metastatic prostate (Pca) and loco-regional disease with high-risk features given the fact that randomized evidence supports the use of ADT in combination with external beam radiation therapy [2, 3]. Recent published studies have conflicting results, making it difficult to draw conclusion on the impact of ADT on dementia and Parkinson’s disease [10,11,12,13]. These discrepancies may have occurred because of important methodologic limitations and errors in statistical interpretation, especially after adjusting confounding variables [11]. Confounding may occur when the false association is created due to differences between patients that are related to both exposure (e.g., treatment assignment) and outcome; for example, patients receiving ADT tend to be older, have low socioeconomic status (SES), and have more comorbidities [11, 12] and these are associated with increased risk of dementia. Results from nationwide datasets should be validated because it does not report clinical variables, such as alcohol consumption, smoking status, and body mass index (BMI)

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