Aging Clin Exp Res DOI 10.1007/s40520-014-0300-5
ORIGINAL ARTICLE
Endogenous sex hormones and cognitive function in the elderly Lisa Boss • Duck-Hee Kang • Nancy Bergstrom J. Leigh Leasure
•
Received: 27 August 2014 / Accepted: 20 November 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Estrogen and testosterone may influence cognitive function in the older adult, but the relationship between sex hormones and cognitive function is complex. Aim To examine associations of sex hormones and cognitive function among older adults C65 years old. Methods Using a cross-sectional research design, data were collected once from 71 elderly (mean age 86.4 years). Global cognitive function and executive function were measured with standardized instruments, and saliva samples were collected for salivary estradiol and testosterone. Results Estradiol was significantly and positively correlated with global cognitive function in men only (r = 0.54, p \ 0.05). Testosterone was not significantly correlated with global cognitive function or executive function in either gender. Discussion and conclusion Associations between sex hormones and cognitive function were mostly non-significant. However, higher estradiol was significantly correlated with better global cognitive function in men, suggesting gender-specific differences. Along with sex hormones, other comorbidity may need to be assessed together in relation to cognitive function in the elderly. Accordingly, clinicians play an important role in educating and promoting beneficial actions to preserve cognitive function.
L. Boss (&) D.-H. Kang N. Bergstrom The University of Texas Health Science Center at Houston, 6901 Bertner, Houston, TX 77030, USA e-mail: [email protected] J. L. Leasure The University of Houston, 126 Heyne Building, Houston, TX 77204, USA
Keywords Elderly
Estradiol Testosterone Cognitive function
Introduction A rapid growth of adults over 65 years of age is a significant concern in the United States. More than 11 million will suffer from cognitive decline, such as dementia or Alzheimer’s disease (AD), in the near future, and the direct and indirect costs related to cognitive decline are estimated to be $148 billion annually [1]. Particularly for the elderly population, cognitive decline indicates the inability to perform independent activities of daily living and everyday functioning, including comprehending medication instructions, handling finances, arranging transportation, and food preparation [2]. Although cognitive decline is common in the elderly, empirical evidence supports that aging brain is capable of neurogenesis and neuroplasticity, refuting the myth that cognitive decline is inevitable with aging [3]. To promote and better preserve the capacity for the elderly to live independently, an important area of research is the examination of the potential factors that can influence cognitive decline. Sex hormones, particularly estrogen and testosterone, may influence cognitive function, however, the effects of age-related changes on brain function are poorly understood [4]. In both genders, estrogen and testosterone have broad influence on various body systems, including reproduction and metabolism. In addition to peripheral actions, estrogen receptors also are found in areas of the brain known for their role in cognitive function and mood, including the cerebral cortex, hypothalamus, pituitary, limbic system, and the frontal, cingulated, and primary olfactory cortices. It is also believed that estrogen promotes
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neurogenesis in the hippocampus and prefrontal cortex, regions associated with memory and executive function [5]. Testosterone may also influence cognitive function and has shown neuroprotective properties by binding with androgen receptors in the brain [6]. In particular, the hippocampus is dense with androgen receptors, and testosterone is thought to reduce neuronal damage caused by oxidative stress in this area. At optimal levels, testosterone may also lessen neuronal apoptosis, increase neuron viability, and defend against formation of amyloid plaques and tangles typically seen in AD [6]. Despite the potential roles of estrogen and testosterone in cognitive function in the elderly, the findings of studies have been mixed. In women with a mean age C60 years, estradiol was positively associated with better episodic memory, semantic memory, and verbal memory [7–9]. However, others reported that higher estradiol was associated with worse executive function in women of similar age [10]. In men with a mean age C60 years, higher estradiol was associated with worse performance in numerous domains of cognitive function, such as working memory and executive function [11–13], whereas higher estradiol was associated with better performance in verbal memory and global cognitive function [14]. The association between testosterone and cognitive function is equally unclear for both genders. Testosterone was positively associated with better performance in global cognitive function, but was negatively associated with worse performance in verbal ability, visual and spatial perception, and reading speed in men C60 years [11, 15]. For women with a mean age C60 years, higher testosterone was associated with better or worse verbal memory, better global cognitive function, worse episodic memory or no significant association [8, 11, 16, 17]. These findings clearly indicate inconsistencies among the studies, suggesting the complex relationship between sex hormones and the specific types of cognitive function, which needs to be studied further in detail [18].
Theoretical framework A biobehavioral interaction model [19] guided this study and provided an overview of potential biological factors influencing cognitive health outcomes. In this model, health outcomes are proposed to be influenced by various factors, such as individual, psychosocial, behavioral, and environmental factors. These factors interact to influence biological responses, which then affect mental and physical health outcomes [19]. In the adapted model, salivary estradiol and testosterone (biological factors) are thought to influence the cognitive health outcomes of global cognitive
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function and executive function in this study. However, given the limitation in the design (one time measurement), the primary focus of this pilot study was to explore correlations between sex hormones and cognitive function. The specific goals of this study were to examine the associations of salivary estradiol and testosterone with global cognitive function and executive function in community dwelling males and females aged 65 years and over. It was hypothesized that both hormones would show positive correlations with global cognitive function and executive function in both genders.
Methods Sample Sample size was calculated using conservative values of effect size set at 0.5, power level set at 0.8, and the correlation coefficient set to detect a moderate to strong Pearson’s r. The estimated, minimum sample size was 60 participants. Inclusion criteria were: (1) C65 years of age, (2) the ability to read/write in English, and (3) no diagnosis of a neurodegenerative disease, such as dementia or AD, based on self-report. Exclusion criteria were: (1) inability to complete psychometric instruments as instructed, (2) inability to provide a saliva sample, and (3) currently taking hormone replacement therapy or corticosteroids. Recruitment Recruitment flyers were posted at a faith-based, non-profit, Continuous Care Retirement Community that provides housing for residents with varying levels of physical and cognitive functioning and includes independent living, assisted living, and long-term care. The study was explained in full detail to potential subjects and questions were answered before obtaining written consent from participants (N = 71). Prior to data collection, this study was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston. Data were collected at one time point for all variables. Each participant received a gift card to the local grocery store in the amount of $20 upon completion of the study. Measurement Cognitive function data were collected using standardized reliable and validated instruments in the participant’s individual apartment at the facility. Data collection took approximately 30–40 min.
Aging Clin Exp Res
Mini mental state examination
Data analysis
Global cognitive function was measured using the mini mental state examination (MMSE), an 11-item questionnaire validated in the elderly population whether institutionalized or community dwelling. The MMSE includes simple tests and problems in the domains of orientation, registration, attention and calculation, recall, and language. Scores C24 are considered normal cognition, and those B23 correlate closely with dementia. The Cronbach’s a is 0.96 [20]. In this study, the Cronbach’s a was 0.50.
Data were verified to ensure data entry accuracy, stored into a secure, password-protected database, and analyzed using SPSS version 21.0 (SPSS Inc., Chicago, USA). All data were examined for sample distribution, and when data were deviated from the normal distribution, data were log transformed. For bivariate correlations, Pearson’s productmoment correlation coefficient was used. A priori p value was set at B0.05.
CLOX I
Results
Executive function was measured with the CLOX I, which is designed to elicit executive function impairment. Participants are first instructed to ‘‘draw a clock that says 1:45. On a blank sheet of paper, set the hands and numbers on the face so that a child could read them.’’ Tested in the elderly population, Cronbach’s a for CLOX I is 0.83 [21]. In this study, Cronbach’s a was 0.86.
Individual characteristics
Saliva samples Biomarkers of estradiol and testosterone were assessed from saliva as this non-invasive technique is practical and easy to implement. Salivary estradiol measured by direct immunoassay is highly correlated to serum estradiol (r = 0.80, p \ 0.001). Similarly, salivary testosterone is highly correlated with serum testosterone (r = 0.96, p \ 0.0001) (Salimetrics, LLC, State Park). Saliva samples were collected on the same day as psychometric measurements between 1:00 p.m. and 5:00 p.m. to control for circadian rhythmicity. Each participant rinsed their mouth, waited 5 min, and collected saliva via passive drool into a small container. Most participants successfully provided approximately 2 mL of saliva within 10–20 min. Samples were transported in a secure cooler with ice pack to the Biosciences Laboratory in the Center for Nursing Research at The University of Texas Health Science Center at Houston. Salivary levels of estradiol and testosterone were batch assayed in duplicate using an enzyme immunoassay kit (Salimetrics, LLC, State Park). To evaluate precision of biological measures, coefficients of variability (CV) were calculated. The intra-assay CV was calculated from the duplicates, whereas the interassay CV was calculated from CVs of different plates per manufacturer instructions. A priori criterion for interassay and intra-assay CV was defined at B10 % (Salimetrics, LLC, State Park). The mean intra-assay CV result for testosterone was 8.4 %. The mean intra-assay result for estradiol was 11.7 %. Inter-assay CV results were 9.9 % for estradiol and 6.4 for testosterone.
The sample was comprised of 71 elderly (Table 1). Age ranged from 70 to 99 years (M = 86.4, SD = 6.35) and were predominately independently living, well-educated (40 % with a baccalaureate degree or higher), Caucasian females who reported few medical problems. The most commonly reported medical conditions were osteoarthritis, hypertension, hypercholesterolemia, and hypothyroidism. Few participants reported depression, anxiety, diabetes, cardiovascular disease, or cancer, and only one reported end stage renal failure with weekly hemodialysis. Most participants reported using less than five prescription medications per day and many reported daily vitamin usage. Descriptives of biological and cognitive function measures Table 2 provides basic descriptive results for psychometric instruments and biologic measurements. There were no missing data. All participants except one scored within the normal range on the MMSE (M = 28.39, SD = 1.79), indicating adequate global cognitive function for almost participants. About 40 % of participants performed poorly on the CLOX I, and this was reflected in the mean scores (M = 10.0, SD = 3.24). Estradiol levels were low overall (M = 1.53 pg/mL, SD = 1.21), but within the expected range for all participants. For testosterone, 35 % of participants showed lower levels than the expected minimum, and one result was higher than the expected maximum level. Correlations of biological and cognitive function variables Table 3 provides Pearson’s r values to reflect associations between biological and cognitive function variables. Global cognitive function and executive function were positively and significantly correlated (r = 0.47, p \ 0.001), as
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Aging Clin Exp Res Table 1 Characteristics of the study population (N = 71) Age (years)
N (%)
Mean
SD
Range
71
86.40
6.35
70–99
14.13
2.41
9–22
55.3 months (4.5 years)
57.7 months (4.75 years)
0.50–240 months (0.5 months–20 years)
Gender Males
14 (22.5 %)
Females
57 (77.5 %)
Race Caucasian
70 (98.6 %)
Hispanic
1 (1.4 %)
Marital status Married
21 (29.6 %)
Widowed
48 (67.6 %)
Divorced Education (years) \HS
2 (2.8 %) 71 3 (4.2 %)
HS
27 (37.5 %)
Associates Bachelors
12 (18.1 %) 22 (30.6 %)
Graduate education
7 (9.6 %)
Living situation Independent
66 (92.9 %)
Assisted
4 (5.63 %)
Extended care
1 (1.4 %)
Time at retirement facility
71
well as estradiol and testosterone (r = 0.72, p \ 0.001). The sex hormones did not significantly correlate with either measure of cognitive function for the overall group. However, bivariate analyses by gender revealed a significant positive correlation between estradiol and global cognitive function in men (r = 0.54, p \ 0.05; Tables 4, 5).
Discussion The hypothesis that salivary estradiol and testosterone would positively correlate with global cognitive function and executive function in elderly males and females was partially supported with a significant and positive correlation between estradiol and global cognitive function in men only. This finding is different from the findings of other studies that failed to find a significant association between estradiol and global cognitive function in older men [13, 22, 23]. In other studies, however, researchers reported significant and negative associations in men [12, 24, 25]. For females, our findings are consistent with studies that reported non-significant findings between estradiol and global cognitive function or executive function [4, 8, 26, 27], but are inconsistent with those of other studies that reported significant positive or negative correlations [10, 20, 23].
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For testosterone, non-significant associations of testosterone and various domains of cognitive function are consistent with the findings of some studies [4, 8, 10, 12, 14, 23, 25, 26, 28–30], but not with other findings. In a few other studies, researchers reported significant positive or negative associations between testosterone and either global cognitive function or executive function in both genders [10, 11, 17, 24, 31]. These mixed findings between sex hormones and cognitive functions suggest the complex interactions between the two. In general, associations between sex hormones and cognitive functions have generated very mixed findings. Methodological differences in research approach may have contributed to inconsistent findings. Differences in study design, insufficiently powered samples, inadequate sample collection and handling of biological specimens, and the usage of a variety of psychometric instruments across studies are the potential factors [32]. Despite mixed findings in this field, cognitive function remains to be a highly important issue for the elderly. Clinicians should pay attention to what factors reduce the risk of cognitive decline and what factors promote and enhance cognitive function in the elderly [33]. In addition to sex hormones, other factors may also detrimentally affect cognitive function in the elderly. Hypertension and diabetes mellitus, for example, are important comorbid
Aging Clin Exp Res Table 2 Descriptive data for psychometric and biologic measures (N = 71) Possible range
Score range
Mean
23–30
28.39
Table 5 Correlation coefficient for biological and cognitive function variables in females (n = 57)
SD GCF
Mini mental state exam
0–30
Males
24–30
Females CLOX I
0–15
1.79
27.28
2.30
23–30
28.67
1.55
2–15
10.00
3.24
Males
2–14
8.21
3.56
Females
2–15
10.43
3.02
0.01–5.25
1.53
1.21
0.02–5.26
1.97
1.43
Estradiol (pg/dL)
\0.35
Males Females Testosterone (pg/mL) Males
48.74–156.5
Females
0.01–5.10
1.42
11.53–171.35
56.43
26.6
1.13
37.34–171.35
69.67
31.87
11.53–109.51
51.51
22.96
Table 3 Correlation coefficient for biological and cognitive function variables (N = 71)
GCF
GCF
EF
1
0.47**
0.16
0.05
1
0.19
-0.04
EF
E2
E2
1
T
T
0.62**
GCF
EF
E2
1
0.39**
0.09
0.09
1
0.16
-0.05
EF E2 T
1
T
0.52** 1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone ** p B 0.01; * p B 0.05 level
well-known risk factor for Alzheimer’s disease [38]. Clinicians are in a unique position to keenly assess these factors and take the needed precaution in a proactive way. Social engagement and participation in cognitively stimulating activities are thought to increase neurogenesis, synaptogenesis, and dendritic complexity [39]. Activities, such as participation in religious activities and various community/recreational activities, are socially engaging and beneficial for seniors [40–42]. Findings from several studies consistently indicate that elderly individuals with higher engagement in cognitively stimulating activities experience less cognitive decline over time [40–42]. Clinicians can take an active role in educating and promoting beneficial actions to help decrease cognitive decline.
1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone
Study limitations
** p B 0.01; * p B 0.05 level
This study has several limitations. The cross-sectional research design limited the data analysis and interpretation to correlational associations between variables but not the causality. The population was very homogenous and a majority of the participants were well-educated and economically comfortable Caucasian females with few medical problems. The small sample size and wide range in age of participants (29 years) may have influenced findings. The sample did not undergo a clinical assessment for dementia, but relied on self-report for diagnosis of neurodegenerative disease. In addition, the MMSE for general cognitive function showed low reliability. For these reasons, the findings of this study should be interpreted with caution. Despite these limitations, we present important insights on correlates of cognitive function in this very old elderly population, which can significantly contribute to the knowledge base of biobehavioral interactions in cognitive function.
Table 4 Correlation coefficient for biological and cognitive function variables in males (n = 14)
GCF
GCF
EF
E2
T
1
0.51
0.54*
0.44
EF E2 T
1
0.40
0.05
1
0.81** 1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone ** p B 0.01; * p B 0.05 level
medical conditions that can influence cognitive function. Chronic elevation of blood pressure reduces brain density in the prefrontal lobes and hippocampus [25, 34], and cognitive decline is reported in approximately one third of adult-onset diabetes [36]. Chronic psychological stress may also affect cognitive function. Stress elevates glucocorticoid levels which are associated with hippocampal synaptic loss, impaired memory, and decreased prefrontal density [37]. Additionally, Apolipoprotein E (ApoE) genotype is a
Conclusions Associations of estradiol and testosterone with cognitive function in the elderly were mostly non-significant, except
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a significant positive correlation between estradiol and global cognitive function in men only. Our findings are similar to the mixed results in the literature of this field, indicating complex interactions between sex hormones and cognitive function. However, as sex hormones are genderspecific, sex-hormone related cognitive functions may also have gender differences. Clinicians should consider the possibility of low sex hormone levels as a contributing factor in elderly patients with decreased cognitive function. In addition, certain comorbidity and psychosocial factors may significantly increase the risk of cognitive decline in the elderly patient. Therefore, clinicians should be alert for detecting potential cognitive decline and factors that may influence cognitive function. Conflict of interest
None.
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ORIGINAL ARTICLE
Endogenous sex hormones and cognitive function in the elderly Lisa Boss • Duck-Hee Kang • Nancy Bergstrom J. Leigh Leasure
•
Received: 27 August 2014 / Accepted: 20 November 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Estrogen and testosterone may influence cognitive function in the older adult, but the relationship between sex hormones and cognitive function is complex. Aim To examine associations of sex hormones and cognitive function among older adults C65 years old. Methods Using a cross-sectional research design, data were collected once from 71 elderly (mean age 86.4 years). Global cognitive function and executive function were measured with standardized instruments, and saliva samples were collected for salivary estradiol and testosterone. Results Estradiol was significantly and positively correlated with global cognitive function in men only (r = 0.54, p \ 0.05). Testosterone was not significantly correlated with global cognitive function or executive function in either gender. Discussion and conclusion Associations between sex hormones and cognitive function were mostly non-significant. However, higher estradiol was significantly correlated with better global cognitive function in men, suggesting gender-specific differences. Along with sex hormones, other comorbidity may need to be assessed together in relation to cognitive function in the elderly. Accordingly, clinicians play an important role in educating and promoting beneficial actions to preserve cognitive function.
L. Boss (&) D.-H. Kang N. Bergstrom The University of Texas Health Science Center at Houston, 6901 Bertner, Houston, TX 77030, USA e-mail: [email protected] J. L. Leasure The University of Houston, 126 Heyne Building, Houston, TX 77204, USA
Keywords Elderly
Estradiol Testosterone Cognitive function
Introduction A rapid growth of adults over 65 years of age is a significant concern in the United States. More than 11 million will suffer from cognitive decline, such as dementia or Alzheimer’s disease (AD), in the near future, and the direct and indirect costs related to cognitive decline are estimated to be $148 billion annually [1]. Particularly for the elderly population, cognitive decline indicates the inability to perform independent activities of daily living and everyday functioning, including comprehending medication instructions, handling finances, arranging transportation, and food preparation [2]. Although cognitive decline is common in the elderly, empirical evidence supports that aging brain is capable of neurogenesis and neuroplasticity, refuting the myth that cognitive decline is inevitable with aging [3]. To promote and better preserve the capacity for the elderly to live independently, an important area of research is the examination of the potential factors that can influence cognitive decline. Sex hormones, particularly estrogen and testosterone, may influence cognitive function, however, the effects of age-related changes on brain function are poorly understood [4]. In both genders, estrogen and testosterone have broad influence on various body systems, including reproduction and metabolism. In addition to peripheral actions, estrogen receptors also are found in areas of the brain known for their role in cognitive function and mood, including the cerebral cortex, hypothalamus, pituitary, limbic system, and the frontal, cingulated, and primary olfactory cortices. It is also believed that estrogen promotes
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neurogenesis in the hippocampus and prefrontal cortex, regions associated with memory and executive function [5]. Testosterone may also influence cognitive function and has shown neuroprotective properties by binding with androgen receptors in the brain [6]. In particular, the hippocampus is dense with androgen receptors, and testosterone is thought to reduce neuronal damage caused by oxidative stress in this area. At optimal levels, testosterone may also lessen neuronal apoptosis, increase neuron viability, and defend against formation of amyloid plaques and tangles typically seen in AD [6]. Despite the potential roles of estrogen and testosterone in cognitive function in the elderly, the findings of studies have been mixed. In women with a mean age C60 years, estradiol was positively associated with better episodic memory, semantic memory, and verbal memory [7–9]. However, others reported that higher estradiol was associated with worse executive function in women of similar age [10]. In men with a mean age C60 years, higher estradiol was associated with worse performance in numerous domains of cognitive function, such as working memory and executive function [11–13], whereas higher estradiol was associated with better performance in verbal memory and global cognitive function [14]. The association between testosterone and cognitive function is equally unclear for both genders. Testosterone was positively associated with better performance in global cognitive function, but was negatively associated with worse performance in verbal ability, visual and spatial perception, and reading speed in men C60 years [11, 15]. For women with a mean age C60 years, higher testosterone was associated with better or worse verbal memory, better global cognitive function, worse episodic memory or no significant association [8, 11, 16, 17]. These findings clearly indicate inconsistencies among the studies, suggesting the complex relationship between sex hormones and the specific types of cognitive function, which needs to be studied further in detail [18].
Theoretical framework A biobehavioral interaction model [19] guided this study and provided an overview of potential biological factors influencing cognitive health outcomes. In this model, health outcomes are proposed to be influenced by various factors, such as individual, psychosocial, behavioral, and environmental factors. These factors interact to influence biological responses, which then affect mental and physical health outcomes [19]. In the adapted model, salivary estradiol and testosterone (biological factors) are thought to influence the cognitive health outcomes of global cognitive
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function and executive function in this study. However, given the limitation in the design (one time measurement), the primary focus of this pilot study was to explore correlations between sex hormones and cognitive function. The specific goals of this study were to examine the associations of salivary estradiol and testosterone with global cognitive function and executive function in community dwelling males and females aged 65 years and over. It was hypothesized that both hormones would show positive correlations with global cognitive function and executive function in both genders.
Methods Sample Sample size was calculated using conservative values of effect size set at 0.5, power level set at 0.8, and the correlation coefficient set to detect a moderate to strong Pearson’s r. The estimated, minimum sample size was 60 participants. Inclusion criteria were: (1) C65 years of age, (2) the ability to read/write in English, and (3) no diagnosis of a neurodegenerative disease, such as dementia or AD, based on self-report. Exclusion criteria were: (1) inability to complete psychometric instruments as instructed, (2) inability to provide a saliva sample, and (3) currently taking hormone replacement therapy or corticosteroids. Recruitment Recruitment flyers were posted at a faith-based, non-profit, Continuous Care Retirement Community that provides housing for residents with varying levels of physical and cognitive functioning and includes independent living, assisted living, and long-term care. The study was explained in full detail to potential subjects and questions were answered before obtaining written consent from participants (N = 71). Prior to data collection, this study was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston. Data were collected at one time point for all variables. Each participant received a gift card to the local grocery store in the amount of $20 upon completion of the study. Measurement Cognitive function data were collected using standardized reliable and validated instruments in the participant’s individual apartment at the facility. Data collection took approximately 30–40 min.
Aging Clin Exp Res
Mini mental state examination
Data analysis
Global cognitive function was measured using the mini mental state examination (MMSE), an 11-item questionnaire validated in the elderly population whether institutionalized or community dwelling. The MMSE includes simple tests and problems in the domains of orientation, registration, attention and calculation, recall, and language. Scores C24 are considered normal cognition, and those B23 correlate closely with dementia. The Cronbach’s a is 0.96 [20]. In this study, the Cronbach’s a was 0.50.
Data were verified to ensure data entry accuracy, stored into a secure, password-protected database, and analyzed using SPSS version 21.0 (SPSS Inc., Chicago, USA). All data were examined for sample distribution, and when data were deviated from the normal distribution, data were log transformed. For bivariate correlations, Pearson’s productmoment correlation coefficient was used. A priori p value was set at B0.05.
CLOX I
Results
Executive function was measured with the CLOX I, which is designed to elicit executive function impairment. Participants are first instructed to ‘‘draw a clock that says 1:45. On a blank sheet of paper, set the hands and numbers on the face so that a child could read them.’’ Tested in the elderly population, Cronbach’s a for CLOX I is 0.83 [21]. In this study, Cronbach’s a was 0.86.
Individual characteristics
Saliva samples Biomarkers of estradiol and testosterone were assessed from saliva as this non-invasive technique is practical and easy to implement. Salivary estradiol measured by direct immunoassay is highly correlated to serum estradiol (r = 0.80, p \ 0.001). Similarly, salivary testosterone is highly correlated with serum testosterone (r = 0.96, p \ 0.0001) (Salimetrics, LLC, State Park). Saliva samples were collected on the same day as psychometric measurements between 1:00 p.m. and 5:00 p.m. to control for circadian rhythmicity. Each participant rinsed their mouth, waited 5 min, and collected saliva via passive drool into a small container. Most participants successfully provided approximately 2 mL of saliva within 10–20 min. Samples were transported in a secure cooler with ice pack to the Biosciences Laboratory in the Center for Nursing Research at The University of Texas Health Science Center at Houston. Salivary levels of estradiol and testosterone were batch assayed in duplicate using an enzyme immunoassay kit (Salimetrics, LLC, State Park). To evaluate precision of biological measures, coefficients of variability (CV) were calculated. The intra-assay CV was calculated from the duplicates, whereas the interassay CV was calculated from CVs of different plates per manufacturer instructions. A priori criterion for interassay and intra-assay CV was defined at B10 % (Salimetrics, LLC, State Park). The mean intra-assay CV result for testosterone was 8.4 %. The mean intra-assay result for estradiol was 11.7 %. Inter-assay CV results were 9.9 % for estradiol and 6.4 for testosterone.
The sample was comprised of 71 elderly (Table 1). Age ranged from 70 to 99 years (M = 86.4, SD = 6.35) and were predominately independently living, well-educated (40 % with a baccalaureate degree or higher), Caucasian females who reported few medical problems. The most commonly reported medical conditions were osteoarthritis, hypertension, hypercholesterolemia, and hypothyroidism. Few participants reported depression, anxiety, diabetes, cardiovascular disease, or cancer, and only one reported end stage renal failure with weekly hemodialysis. Most participants reported using less than five prescription medications per day and many reported daily vitamin usage. Descriptives of biological and cognitive function measures Table 2 provides basic descriptive results for psychometric instruments and biologic measurements. There were no missing data. All participants except one scored within the normal range on the MMSE (M = 28.39, SD = 1.79), indicating adequate global cognitive function for almost participants. About 40 % of participants performed poorly on the CLOX I, and this was reflected in the mean scores (M = 10.0, SD = 3.24). Estradiol levels were low overall (M = 1.53 pg/mL, SD = 1.21), but within the expected range for all participants. For testosterone, 35 % of participants showed lower levels than the expected minimum, and one result was higher than the expected maximum level. Correlations of biological and cognitive function variables Table 3 provides Pearson’s r values to reflect associations between biological and cognitive function variables. Global cognitive function and executive function were positively and significantly correlated (r = 0.47, p \ 0.001), as
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Aging Clin Exp Res Table 1 Characteristics of the study population (N = 71) Age (years)
N (%)
Mean
SD
Range
71
86.40
6.35
70–99
14.13
2.41
9–22
55.3 months (4.5 years)
57.7 months (4.75 years)
0.50–240 months (0.5 months–20 years)
Gender Males
14 (22.5 %)
Females
57 (77.5 %)
Race Caucasian
70 (98.6 %)
Hispanic
1 (1.4 %)
Marital status Married
21 (29.6 %)
Widowed
48 (67.6 %)
Divorced Education (years) \HS
2 (2.8 %) 71 3 (4.2 %)
HS
27 (37.5 %)
Associates Bachelors
12 (18.1 %) 22 (30.6 %)
Graduate education
7 (9.6 %)
Living situation Independent
66 (92.9 %)
Assisted
4 (5.63 %)
Extended care
1 (1.4 %)
Time at retirement facility
71
well as estradiol and testosterone (r = 0.72, p \ 0.001). The sex hormones did not significantly correlate with either measure of cognitive function for the overall group. However, bivariate analyses by gender revealed a significant positive correlation between estradiol and global cognitive function in men (r = 0.54, p \ 0.05; Tables 4, 5).
Discussion The hypothesis that salivary estradiol and testosterone would positively correlate with global cognitive function and executive function in elderly males and females was partially supported with a significant and positive correlation between estradiol and global cognitive function in men only. This finding is different from the findings of other studies that failed to find a significant association between estradiol and global cognitive function in older men [13, 22, 23]. In other studies, however, researchers reported significant and negative associations in men [12, 24, 25]. For females, our findings are consistent with studies that reported non-significant findings between estradiol and global cognitive function or executive function [4, 8, 26, 27], but are inconsistent with those of other studies that reported significant positive or negative correlations [10, 20, 23].
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For testosterone, non-significant associations of testosterone and various domains of cognitive function are consistent with the findings of some studies [4, 8, 10, 12, 14, 23, 25, 26, 28–30], but not with other findings. In a few other studies, researchers reported significant positive or negative associations between testosterone and either global cognitive function or executive function in both genders [10, 11, 17, 24, 31]. These mixed findings between sex hormones and cognitive functions suggest the complex interactions between the two. In general, associations between sex hormones and cognitive functions have generated very mixed findings. Methodological differences in research approach may have contributed to inconsistent findings. Differences in study design, insufficiently powered samples, inadequate sample collection and handling of biological specimens, and the usage of a variety of psychometric instruments across studies are the potential factors [32]. Despite mixed findings in this field, cognitive function remains to be a highly important issue for the elderly. Clinicians should pay attention to what factors reduce the risk of cognitive decline and what factors promote and enhance cognitive function in the elderly [33]. In addition to sex hormones, other factors may also detrimentally affect cognitive function in the elderly. Hypertension and diabetes mellitus, for example, are important comorbid
Aging Clin Exp Res Table 2 Descriptive data for psychometric and biologic measures (N = 71) Possible range
Score range
Mean
23–30
28.39
Table 5 Correlation coefficient for biological and cognitive function variables in females (n = 57)
SD GCF
Mini mental state exam
0–30
Males
24–30
Females CLOX I
0–15
1.79
27.28
2.30
23–30
28.67
1.55
2–15
10.00
3.24
Males
2–14
8.21
3.56
Females
2–15
10.43
3.02
0.01–5.25
1.53
1.21
0.02–5.26
1.97
1.43
Estradiol (pg/dL)
\0.35
Males Females Testosterone (pg/mL) Males
48.74–156.5
Females
0.01–5.10
1.42
11.53–171.35
56.43
26.6
1.13
37.34–171.35
69.67
31.87
11.53–109.51
51.51
22.96
Table 3 Correlation coefficient for biological and cognitive function variables (N = 71)
GCF
GCF
EF
1
0.47**
0.16
0.05
1
0.19
-0.04
EF
E2
E2
1
T
T
0.62**
GCF
EF
E2
1
0.39**
0.09
0.09
1
0.16
-0.05
EF E2 T
1
T
0.52** 1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone ** p B 0.01; * p B 0.05 level
well-known risk factor for Alzheimer’s disease [38]. Clinicians are in a unique position to keenly assess these factors and take the needed precaution in a proactive way. Social engagement and participation in cognitively stimulating activities are thought to increase neurogenesis, synaptogenesis, and dendritic complexity [39]. Activities, such as participation in religious activities and various community/recreational activities, are socially engaging and beneficial for seniors [40–42]. Findings from several studies consistently indicate that elderly individuals with higher engagement in cognitively stimulating activities experience less cognitive decline over time [40–42]. Clinicians can take an active role in educating and promoting beneficial actions to help decrease cognitive decline.
1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone
Study limitations
** p B 0.01; * p B 0.05 level
This study has several limitations. The cross-sectional research design limited the data analysis and interpretation to correlational associations between variables but not the causality. The population was very homogenous and a majority of the participants were well-educated and economically comfortable Caucasian females with few medical problems. The small sample size and wide range in age of participants (29 years) may have influenced findings. The sample did not undergo a clinical assessment for dementia, but relied on self-report for diagnosis of neurodegenerative disease. In addition, the MMSE for general cognitive function showed low reliability. For these reasons, the findings of this study should be interpreted with caution. Despite these limitations, we present important insights on correlates of cognitive function in this very old elderly population, which can significantly contribute to the knowledge base of biobehavioral interactions in cognitive function.
Table 4 Correlation coefficient for biological and cognitive function variables in males (n = 14)
GCF
GCF
EF
E2
T
1
0.51
0.54*
0.44
EF E2 T
1
0.40
0.05
1
0.81** 1
GCF global cognitive function, EF executive function, E2 estradiol, T testosterone ** p B 0.01; * p B 0.05 level
medical conditions that can influence cognitive function. Chronic elevation of blood pressure reduces brain density in the prefrontal lobes and hippocampus [25, 34], and cognitive decline is reported in approximately one third of adult-onset diabetes [36]. Chronic psychological stress may also affect cognitive function. Stress elevates glucocorticoid levels which are associated with hippocampal synaptic loss, impaired memory, and decreased prefrontal density [37]. Additionally, Apolipoprotein E (ApoE) genotype is a
Conclusions Associations of estradiol and testosterone with cognitive function in the elderly were mostly non-significant, except
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Aging Clin Exp Res
a significant positive correlation between estradiol and global cognitive function in men only. Our findings are similar to the mixed results in the literature of this field, indicating complex interactions between sex hormones and cognitive function. However, as sex hormones are genderspecific, sex-hormone related cognitive functions may also have gender differences. Clinicians should consider the possibility of low sex hormone levels as a contributing factor in elderly patients with decreased cognitive function. In addition, certain comorbidity and psychosocial factors may significantly increase the risk of cognitive decline in the elderly patient. Therefore, clinicians should be alert for detecting potential cognitive decline and factors that may influence cognitive function. Conflict of interest
None.
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