Levels of sex hormones have limited effect on cognition in older men with or without prostate cancer

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Abstract

Androgen deprivation therapy is commonly used to treat prostate cancer, but by lowering testosterone levels it may affect cognitive function. However, the relationship between testosterone and cognition remains unclear. We examined the relationship between sex hormones (total testosterone, bioavailable testosterone, and estradiol) and cognition in a cross-sectional study of 198 older men (mean age 69.2 years, median education 16 years) with and without prostate cancer, none of who had started androgen deprivation therapy. We found relationships between total testosterone and two of four measures of working memory. Similar relationships were found in regression analyses adjusted for age and education with both total testosterone and estradiol. Neither hormone was related to other cognitive domains, nor was bioavailable testosterone level. Although cognitive function was not generally related to sex hormone levels in older men, there may be a weak association with working memory. These results may help guide future studies.

Introduction

An increasing number of men with both early and late prostate cancer are receiving androgen deprivation therapy (ADT) [1]. However, there is emerging evidence that a lack of androgens (as seen with ADT use) may adversely affect cognition. In a study by Green et al. [2], 6 months of ADT was associated with declines in memory, attention and executive function. Subsequent studies in men receiving ADT demonstrated declines in spatial rotation [3], sustained attention [3], visual memory [4], and verbal memory [5], but other studies have demonstrated no impact on various cognitive domains [6], [7] or even improvement in selected domains [2], [8]. A recently published systematic review suggested that visuo-spatial abilities and executive functioning may be most vulnerable to the effects of ADT, but also noted that studies have reported some contradictory results and have been limited by small sample sizes [9]. Projections suggest that up to 1 in 2 men with prostate cancer will receive ADT at some point after diagnosis [1], so that clarifying the relationship between ADT and cognitive function remains important.

Several studies have investigated relationships between sex hormones and cognitive performance in elderly men without prostate cancer. For example, a large (n = 407) longitudinal study indicated that higher testosterone levels correlate positively with visuo-spatial abilities, verbal and visual memory [10]. However, other large studies (n > 500) have suggested that there is no significant correlation between sex hormones and cognitive performance in elderly males [11], [12], [13]. Furthermore, the results of smaller testosterone supplementation studies have also revealed inconsistent results: five studies found that testosterone supplementation improved visuo-spatial memory [14], [15], [16], [17], verbal memory [14], [15], and working memory [18], whereas three studies did not demonstrate improvements in cognition in older men [19], [20], [21]. Thus, the relationship between sex hormones and cognitive function remains unclear.

Research into cognitive effects of treatment among cancer patients has been plagued by methodological issues [22]. Chief among these is selecting the appropriate set of neuropsychological measures to minimize patient burden while maximizing the likelihood of detecting subtle cognitive changes.

Given the conflicting findings from prior studies, further studies will be needed to clarify the cognitive effects of ADT in men with prostate cancer. Our group is conducting a longitudinal study to understand whether ADT use is associated with cognitive changes. Recognizing that comprehensive neuropsychological evaluation can be resource-intensive and burdensome to patients, we performed this cross-sectional analysis of baseline data from the longitudinal study to gain insight into which domains of cognitive function might be most sensitive to variations in levels of sex hormones in a cohort of older men, with and without prostate cancer, who were not taking ADT. These results may help guide the design of future studies examining the relationship between ADT and cognitive function.

Section snippets

Study population

Subjects (N = 253 men, 85 men with non-metastatic prostate cancer who were about to start ADT, 84 men with non-metastatic prostate cancer who were not on ADT, and 84 healthy controls) were participants in a larger, prospective matched cohort study to examine the impact of ADT on health outcomes including cognitive function. Subjects were recruited from the Prostate Centre at the University Health Network/Princess Margaret Hospital, a tertiary care comprehensive cancer center. Patients with

Results

A total of 253 men were recruited to the study. Participants who refused to have blood work drawn (n = 8), scored lower than 24/30 on the MMSE (n = 1) or who had already started ADT (n = 43) were excluded. An additional 3 men missed their initial cognitive assessment. Thus, 198 men (with mean MMSE and NAART scores of 28 and 110, respectively) were included in the analyses (Table 2). Patients were generally highly educated (median 16 years of education). Three participants (2%) included in the

Discussion

Using a cross-sectional design among a group of well-educated older men with and without prostate cancer, all of whom had non-castrate levels of male sex hormones and none of whom were on ADT, we found few correlations between serum sex hormone levels and cognitive function. Although a weak association was noted between BT and a measure of verbal learning and memory as well as a measure of cognitive flexibility, these were no longer significant after adjustment for age and education. An

Reviewers

Supriya Gupta Mohile, M.D., M.S., Assistant Professor, University of Rochester, Department of Medicine, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, United States.

Heather J. Green, Ph.D., Lecturer in Clinical Psychology, Griffith University, School of Psychology, Griffith University Gold Coast Campus, Gold Coast, QLD 4222, Australia.

Conflict of interest

None of the authors have any financial conflicts of interest to declare with respect to this manuscript.

Acknowledgement

Ms. Mahmoud and this study were supported by a grant from the Canadian Cancer Society Research Institute. Dr. Alibhai is a Research Scientist of the Canadian Cancer Society Research Institute.

Dr. Shabbir Alibhai is an Assistant Professor in the Departments of Medicine and Health Policy, Management, and Evaluation at the University of Toronto. He is a staff physician and researcher at the University Health Network and Toronto Rehabilitation Institute, and a Research Scientist of the National Cancer Institute of Canada. His research interests are in geriatric oncology, particularly in understanding and improving quality of life, fatigue, and related health domains in older people with

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    Dr. Shabbir Alibhai is an Assistant Professor in the Departments of Medicine and Health Policy, Management, and Evaluation at the University of Toronto. He is a staff physician and researcher at the University Health Network and Toronto Rehabilitation Institute, and a Research Scientist of the National Cancer Institute of Canada. His research interests are in geriatric oncology, particularly in understanding and improving quality of life, fatigue, and related health domains in older people with prostate cancer and acute leukemia.

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