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Association between endogenous sex hormone levels and cognition: the Women’s Isoflavone Soy Health (WISH) trial
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Association between endogenous sex hormone levels and cognition: the Women’s Isoflavone Soy Health (WISH) trial
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1 ASSOCIATION BETWEEN ENDOGENOUS SEX HORMONE LEVELS AND COGNITION: THE WOMEN’S ISOFLA VONE SOY HEALTH (WISH) TRIAL By Han Gao A Thesis Presented to the FACULTY OF THE GRADUA TE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOSTA TISTICS) December 2015 Copyright 2015 Han Gao 2 ACKNOWLEDGEMENTS I want to thank Dr. Wendy Mack, my committee chair for her patient and kindly help during the thesis development. I also want to express my appreciation to my committee members Dr. Howard Hodis and Dr. Roksana Karim for their kindly support for my thesis. Thank you for all the supports from my parents and my friends. 3 TABLE OF CONTENTS ACKNOWLEDGEMENTS ......................................................................... 2 LIST OF TABLES ....................................................................................... 4 ABSTRACT ................................................................................................ 5 INTRODUCTION ....................................................................................... 6 METHODS .................................................................................................. 8 RESULTS ...................................................................................................13 DISCUSSION .............................................................................................30 CONCLUSION ..........................................................................................31 REFERENCES ...........................................................................................33 APPENDIX ................................................................................................39 4 LIST OF TABLES Table 1.Visits Excluded for Hormones Variables ...................................16 Table 2.Summary of Hormone Levels in Analytic Dataset ....................16 Table 3.WISH Participant Characteristics at Baseline (n=307) ..............18 Table 4.Association between Demographic Variables and 2.5-Year Change in Cognitive Function ...................................21 Table 5.Association Between Demographic Variables and Hormone levels .......................................................................24 Table 6. Association of Baseline Hormones with Baseline Cognition.................................................................................28 Table 7. Association between Hormones and 2.5-Year Change in Cognitive Functions ................................................29 5 ABSTRACT Objective: The purpose of this study was to assess the association between endogenous levels of hormones and changes in cognitive function measured over 2.5 years among postmenopausal women. Methods: The Women’s Isoflavone Soy Health (WISH) trial was a randomized, double-blind and placebo-controlled trial. A total of 350 postmenopausal women were randomized to isoflavone soy protein (ISP) or placebo groups and followed on their randomized intervention for 30 months. The panel of fasting plasma levels of sex steroid hormones included progesterone (pg/ml), estradiol (pg/ml), estrone (pg/ml), prolactin (ng/ml), total testosterone (pg/ml) and free testosterone (pg/ml). Sex hormone binding globulin (SHBG, nmol/L) was also measured. Neuropsychological tests were selected to measure a broad spectrum of cognitive abilities. Participants were tested before randomized intervention and at the study endpoint, approximately 2.5 years later. Changes in cognition were summarized as endpoint values minus baseline values. Associations of changes in cognitive function were evaluated with endogenous levels of hormones using multiple linear regression models. Associations of baseline levels of cognitive variables with baseline levels of hormone levels used linear regression models, adjusting for age and education. Evaluation of 6 collinearity, correlation structure and model assumptions were performed to ensure model validity. Result: There were no significant associations between any baseline hormone levels and any cognitive functions; the associations of baseline total testosterone with baseline global cognition and baseline verbal memory were of borderline significance (p=0.06). Consistent with the association of baseline hormones with baseline cognition, there were no significant associations between hormone levels and change in global cognition or other cognitive functions; the association of average estradiol with change in executive functions was borderline significant (p=0.08). Conclusion: We failed to support the hypothesis that sex hormone levels measured by serum concentrations are related to verbal memory, executive functions or global cognition. Similarly, the cumulative exposures of hormone levels are not related to change in cognitive factors or global cognition over an average 2.7-year period. 7 INTRODUCTION Levels of sex hormones change with aging and after menopause. Estradiol and estrone concentrations in women decline in the perimenopause and reach permanent low postmenopausal levels after the final menstrual period. (Judd and Fournet, 1994; Guthrie et al., 2004). Levels of testosterone decline gradually during a woman’s reproductive years; testosterone levels generally do not change after natural menopause (Davison et al., 2005). As a target organ for steroid hormones, the brain contains receptors for estrogen and testosterone. However, the effects of hormones on the brain are not fully understood. Since estradiol influences the central nervous system, estradiol levels may affect cognitive performance (Rubinow et al., 1996; McEwen et al., 1997; McEwen et al., 1998; Sternbach, 1998; McEwen et al., 1999). Poor memory and trouble concentrating are common midlife cognitive complaints (Mitchell and Woods, 2001; Simon and Reape, 2009). It is not clear whether and to what extent the menopause-related reduction in ovarian hormones influences midlife cognitive outcomes. Few studies have evaluated associations between serum estradiol and other hormone levels in postmenopausal women and cognitive functions (Herlitz et al., 2007; Ryan et al., 2010). Studies that have tested these associations report inconsistent results. Some observational studies support a 8 positive association between use of hormone replacement on cognitive function; however results of randomized controlled trials have not demonstrated cognitive benefit (Henderson and Sherwin, 2007; Lethaby et al., 2008). Some studies even suggest a mild cognitive detriment associated with estrogen-based hormone therapy (Espeland et al., 2004; Maki et al., 2007). While the cognitive effects of exogenous hormones remain unclear, the question of whether endogenous serum levels of these hormones influence cognitive performance also remains uncertain. Therefore, using data from The Women’s Isoflavone Soy Health (WISH) trial, we explored whether endogenous levels of hormones influence changes in cognitive function measured over 2.5 years in postmenopausal women. METHODS Study Design and Population Conducted from April 12, 2004, to March 19, 2009, WISH was a randomized, double-blind, placebo-controlled trial. The University of Southern California Institutional Review Board approved the study protocol. Participants were recruited from the general population from the Greater Los Angeles area predominantly through media advertisement (Hodis HN, et al., 2011). 9 Participants were postmenopausal women, without vaginal bleeding >1 year, and serum estradiol <20 pg/mL. Women were excluded who had any of clinical signs, symptoms, or personal history of CVD, diabetes mellitus, fasting serum glucose >126 mg/dL, fasting triglycerides >500 mg/dL, systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg, untreated thyroid disease, serum creatinine >2 mg/dL, life-threatening illness with prognosis <5 years, alcohol intake >5 drinks/day, substance abuse, taking menopausal hormone therapy or soy, nut, or soy-related food allergies. Three hundred fifty healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo (0 mg isoflavones). The planned treatment period was 2.5 years. Comparison of the effect of ISP with that of placebo on the progression of subclinical atherosclerosis was the primary endpoint of the WISH trial. The effect of ISP on cognitive change in 313 women who had baseline and endpoint cognitive test data was a secondary endpoint (Hodis HN, et al., 2011). 10 Cognitive Assessment Neuropsychological tests (Appendix, Table A) were selected to measure a broad spectrum of cognitive abilities. Cognitive ability (verbal intelligence quotient) was estimated at baseline using the Wechsler Test of Adult Reading; mood was assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff LS, 1977). The individual cognitive tests were used to calculate a weighted sum of Z scores for a global cognitive composite , weighted verbal memory composite and weighted executive function composite scores. Participants were tested before randomized intervention and at the study endpoint, approximately 2.5 years later. Changes in cognition were summarized as endpoint values minus baseline values. Hormone Assessment The panel of fasting plasma levels of sex steroid hormones included progesterone (pg/ml), estradiol (pg/ml), estrone (pg/ml), prolactin (ng/ml), total testosterone (pg/ml) and free testosterone (pg/ml). Sex hormone binding globulin (SHBG, nmol/L) was also measured. Progesterone, estradiol, estrone, prolactin, and SHBG were obtained at randomization and at 12 and 30 months post-randomization. Total testosterone and free 11 testosterone were obtained at randomization and 12 months post-randomization. Demographic Characteristics Demographic information including age, marital status, employment status, race, formal education and family annual income were collected at randomization using a structured questionnaire. Statistical Analysis A composite score for global cognition was calculated as a weighted average of the standardized scores for each of 14 individual neuropsychological tests (weighted by the inverse of the correlations between tests). Neuropsychological test data were standardized ([raw score minus mean]/standard deviation) using the baseline means and standard deviations from the entire sample. The executive functions composite score consisted of standardized scores from 8 of 14 tests, including Symbol Digit Modalities Test, Trail Making Test, Part B, Shipley Abstraction, Letter-Number Sequencing, Block Design, Judgment of Line Orientation, Category Fluency, and Boston Naming Test. The verbal memory composite consisted of standardized scores from the California Verbal Learning Test, immediate and recall, and the East Boston Memory Test, immediate and delayed recall. Changes in cognition (endpoint minus baseline) were 12 computed for global composite, executive functions and verbal memory. Multivariable linear regression was used to evaluate the associations between hormone levels and SHBG and baseline and changes in the cognitive composite scores (global cognition, executive functions and verbal memory), the dependent variables in the linear regression models. Except for SHBG, the six hormone variables showed no significant changes over the study visits. Therefore, we simply averaged the values over the visits among the six hormone variables as independent variables in the linear regression models. The baseline of SHBG and change of SHBG (the average of the 12 month visit minus baseline values and 30 month visit minus baseline values) were used as summary measures of SHBG. Regression models were also adjusted for the baseline value of the cognitive score. Demographic characteristics, including age, formal education, family annual income, race, employment status and marital status were considered as possible confounders of the association of hormone levels with cognitive change. These variables were included in the regression model as confounders if they changed the regression coefficient of interest (the association between hormone and cognitive change) by more than 10%. To check for violations of model assumptions we used residual analysis. A histogram of model residuals was used to check whether the regression model residuals were distributed normally. The linearity assumption was 13 graphically evaluated using a scatterplot of model residuals versus model-predicted values. To evaluate homogeneity of variables, residuals were plotted against each predictor. RESULTS Analysis Dataset: Figure 1 summarizes the participant/data flow for this analysis dataset. A total of 1063 community volunteers were screened for eligibility; 350 women were randomly assigned into the trial. Among the randomized women, 313 women had both baseline and end point cognitive test data; six participants were excluded from this analysis because they used hormone therapy during the trial. Therefore, 307 participants were included in these analyses. Hormone Data: Complete hormone data were not available for all 307 participants (summarized in Figure 1). Thirteen women had no prolactin measures at any visit, and 40 women had no testosterone measurements. 307 women had at least one progesterone, estradiol, estrone, and SHBG measurement. One participant was an outlier on estradiol and estrone, leaving 306 women with at least one measurement for estradiol and estrone. 294 women had at least one prolactin measurement, and 267 women had at least one testosterone measurement during the trial. All hormone measurements were compared to normal ranges for postmenopausal women (normal ranges provided by Dr. Frank Stanczyk, 14 Table 2). Visits with a measured value that was more than twice the upper limit of the normal range were excluded from the analysis as shown below (Table 1). These hormone values were excluded from the analytic dataset; hormone measurements included in the analytic dataset are summarized in Table 2. Cognitive Data: Of the 307 women included in this analysis, the average (SD) time between baseline and follow-up cognitive testing was 2.7 (0.17) years, with a range of 2-3.4 years. Baseline Characteristics of Analysis Sample: Participants were primarily non-Hispanic white (191, 62.2%) with a mean (SD) age of 60.6 (7.1). More than half, 183 (59.6%), were college graduates, 171 (55.7%) were not employed and 175 (55.7%) were married (Table 3). Associations of Demographic Variables with Cognitive Change: Change in global cognition, measured over an average of 2.7 years, was not associated with years of formal education, employment or race (all P≥0.16, Table 4). Change in global cognition was significantly negatively associated with age (P<0.001). Per year of age, global cognition in this sample of postmenopausal women declined 0.043 units (95% CI = -0.059, -0.026) over the study period. Marital status (P=0.014; Table 4) was also significantly associated with change in global cognition. Average global cognitive change of single or never married postmenopausal women was 0.204 units (95% 15 CI=-0.219, 0627) higher, and of separated, divorced, and widowed women was 0.270 units (95% CI=-0.533, -0.008) lower than married women. Figure 1.Flow diagram for analysis dataset 350 Participated 313 completed the study (cognitive assessment at baseline and endpoint) 37 did not complete the study 307 included in analysis 1063 Assessed for eligibility 713 Excluded 660 Not meeting inclusion criteria 53 Declined to Measurement for Progesterone, Estradiol, Estrone: 271 completed at visit 0, 12, 30 6 completed at visit 0, 12 30 completed at visit 0 only. Measurement for SBHG: 257 completed at visit 0, 12 and 30 21 completed at visit 0 and 12 29 completed at visit 0 only. Measurement for prolactin: 255 completed at visit 0, 12, 30 8 completed at visit 0, 12 29 completed at visit 0 only 1 completed at visit 12, 30 1 completed at visit 30 13 not complete at visit 0, 12, 30 Measurement for total and free testosterone: 265 completed at visit 0, 12 2 completed only at visit 0 40 not complete at visit 0, 12, 30 6 took estrogen during the trial 16 Table 1.Visits Excluded for Hormones Variables Variables Visit Value Unit Progesterone V-12 2465.63 pg/ml SHBG V-30 318 nmol/l Estradiol V-12 184.53 pg/ml Estradiol V-00 98.88 pg/ml Estradiol V-00 560.48 pg/ml Estrone V-12 187.00 pg/ml Estrone V-00 162.85 pg/ml Estrone V-00 250.41 pg/ml Estrone V-12 199.56 pg/ml Estrone V-30 268.55 pg/ml Estrone V-30 164.70 pg/ml Free Testosterone V-12 16.81 pg/ml Free Testosterone V-00 20.81 pg/ml Free Testosterone V-12 20.19 pg/ml Free Testosterone V-12 16.48 pg/ml Free Testosterone V-00 14.04 pg/ml Free Testosterone V-00 13.98 pg/ml Free Testosterone V-12 13.45 pg/ml Table 2.Summary of Hormone Levels in Analytic Dataset Hormone Variable n Mean Median Minimum Maximum Normal range Total Testosterone 267 254.36 228.53 58.19 991.20 50-500pg/ml Free Testosterone 266 4.73 4.49 1.10 13.22 0.6-6.7pg/ml Progesterone 307 52.59 44.36 15.06 500.55 <400pg/ml Estradiol 306 8.85 8.10 3.57 24.78 <25pg/ml Estrone 306 34.40 32.03 11.92 78.24 15-55pg/ml Prolactin 294 2.09 1.46 0.25 25.07 1.9-25ng/ml Baseline of SHBG 307 48.90 43.20 11.00 130.00 18-114nmol/l Change of SHBG 278 -3.84 -2.92 -34.65 30.50 Hormone values for individual participants are means over all trial visits with hormone data 17 Associations of Demographic Variables with Cognitive Change: Change in global cognition, measured over an average of 2.7 years, was not associated with years of formal education, employment or race (all P≥0.16, Table 4). Change in global cognition was significantly negatively associated with age (P<0.001). Per year of age, global cognition in this sample of postmenopausal women declined 0.043 units (95% CI = -0.059, -0.026) over the study period. Marital status (P=0.014; Table 4) was also significantly associated with change in global cognition. Average global cognitive change of single or never married postmenopausal women was 0.204 units (95% CI=-0.219, 0627) higher, and of separated, divorced, and widowed women was 0.270 units (95% CI=-0.533, -0.008) lower than married women. 18 Table 3.WISH Participant Characteristics at Baseline (n=307) Characteristic Age, mean±SD 60.6±7.1 Formal Education, n (%) Less than high school or high school 15(4.9) Some college 109(35.5) College graduate 183(59.6) Family Annual Income, n (%) Under 29,000 52(16.9) 30,000-59,000 67(21.8) 60,000-89,000 57(18.6) 90,000 and higher 106(34.5) Not reported 25(8.1) Race, n (%) White, non-Hispanic 191(62.2) Black, non-Hispanic 19(6.2) Hispanic 49(16.0) Asian 36(11.7) Other 12(3.9) Employment Status, n (%) Employed 136(44.3) Not employed 1 171(55.7) Marital Status, n (%) Single, never married 29(9.4) Married, marital situation 175(57.0) Separated, Divorced, Widowed 103(33.6) SHBG, nmol/L, mean±SD 48.9±24.3 Hormones, units, mean±SD Progesterone, pg/mL 52.3±36.2 Estradiol, pg/mL 11.0±32.1 Estrone, pg/mL 35.7±19.0 Total Testosterone, pg/ml 257.8±134.9 Free Testosterone, pg/ml 4.8±2.4 Prolactin, ng/L, mean±SD 2.1±2.5 Baseline neuropsychological composite scores, mean±SD (range) Global cognition, weighted 0.03±1.7 (-5.9, 4.4) Verbal memory, weighted 0.01±1.3 (-5.8, 2.9) Executive function, weighted 0.03±1.3 (-4.5, 3.0) 1 Retired, disability, unemployed and other are included in the not employed category 19 Age was also significantly negatively associated with verbal memory (P=0.004, Table 4). Per year of age, verbal memory declined 0.027 units (95% CI=-0.045, -0.008). Formal education was significantly inversely associated with change in verbal memory (p=0.036). Compared to college graduates, women with less than high school or high school graduate education were 0.367 units (95% CI=-0.992, 0.257) lower, and women with some college were 0.288 units (95% CI=-0.567, -0.010) lower on verbal memory change. Marital status was also significantly associated with the change in verbal memory (P=0.046, Table 4); compared to currently married women, single or never married women were 0.255 units (95% CI=-0.199, 0.709) higher and divorced women were 0.200 units (95% CI=-0.484, 0.084) lower. Change in executive functions over the trial was significantly associated only with formal education (P=0.014, Table 4). Compared to college graduates, women with less than high school or high school education were 0.333 units (95% CI=-0.733, 0.067) lower and women with some college were 0.199 units (95% CI=-0.380, -0.019) lower on change in executive functions. Associations of Demographic Variables with Endogenous Hormone Levels: Age was positively associated with total testosterone (P=0.001, Table 5) and baseline SHBG (P<0.001). Age was not significantly associated 20 with the other hormone variables (all P>0.075). Education was inversely associated with estrone levels. Compared to women with a college education, women who had less than high school or high school education had 3.717 pg/ml (95% CI=-2.387, 9.820) of estrone higher, and women with some college education had 3.773 pg/ml (95% CI=1.021, 6.524) higher estrone levels on average. Formal education was not significantly associated with the other hormones (all P>0.14, Table 5). Women who were employed had total testosterone levels that were on average 31.077 pg/ml (95% CI=0.777, 61.377) lower than women who were not employed (P=0.044) and prolactin levels that were 0.782 ng/ml (95% CI=-1.359, -0.205) higher than women who were not employed. The associations between total testosterone or prolactin and employment were evaluated for confounding by age. In the model adjusted for age, total testosterone was not significantly associated with employment (P=0.44), but prolactin was still significantly associated with employment (P=0.008). Employment was not significantly associated with the other hormones (all P>0.06, Table 5). 21 Table 4.Association between Demographic Variables and 2.5-Year Change in Cognitive Function Demogra phic Variable Value Coefficients 1 df P value 95% CI for P a value STD Lower Bound Upper Bound Dependent Variable: Change in Global Cognition, N=307 Age -0.043 0.009 <0.001 -0.059 -0.026 Formal Education high school or less -0.224 0.299 0.45 -0.811 0.364 . Some college -0.187 0.133 0.16 -0.449 0.075 College graduate (referent) 0.16 Employ Not employed (referent) 0.38 Employed -0.109 0.125 0.38 -0.355 0.137 Marital Status Married (referent) 0.014 never married 0.204 0.215 0.34 -0.219 0.627 . Separated -0.270 0.133 0.044 -0.533 -0.008 Race White, non-Hispanic (referent) 0.68 Black, non-Hispanic -0.212 0.262 0.42 -0.728 0.304 Hispanic -0.024 0.178 0.89 -0.375 0.328 Asian 0.093 0.198 0.64 -0.297 0.482 Other 0.253 0.323 0.43 -0.384 0.889 Dependent variable: Change in Verbal Memory, N=307 Age -0.027 0.009 0.004 -0.045 -0.008 Formal Education high school or less -0.367 0.317 0.25 -0.992 0.257 Some college -0.288 0.142 0.042 -0.567 -0.010 College graduate (referent) 0.036 Employ Not employed (referent) 0.53 Employed -0.084 0.133 0.53 -0.346 0.178 Marital Status Married (referent) 0.046 never married 0.255 0.231 0.27 -0.199 0.709 . Separated -0.200 0.144 0.17 -0.484 0.084 Race White, non-Hispanic (referent) 0.56 Black, non-Hispanic 0.093 0.281 0.74 -0.461 0.646 Hispanic -0.134 0.190 0.48 -0.508 0.240 Asian -0.050 0.213 0.82 -0.469 0.370 Other 0.143 0.348 0.68 -0.542 0.827 Dependent variable: Change in Executive Functions, N=307 Age -0.009 0.006 0.14 -0.021 0.003 Formal Education high school or less -0.333 0.203 0.10 -0.733 0.067 . Some college -0.199 0.092 0.030 -0.380 -0.019 22 College graduate (referent) 0.014 Employ Not employed (referent) 0.64 Employed 0.040 0.086 0.64 -0.129 0.208 Marital Status Married (referent) 0.93 never married -0.172 0.149 0.25 -0.465 0.120 Separated -0.088 0.092 0.34 -0.270 0.094 Race White, non-Hispanic (referent) 0.92 Black, non-Hispanic -0.002 0.181 0.99 -0.358 0.354 Hispanic -0.020 0.125 0.87 -0.266 0.226 Asian 0.081 0.137 0.55 -0.188 0.350 Other 0.076 0.222 0.73 -0.362 0.514 Beta estimates are from linear regression models, with change in the cognitive composite score as the dependent variable. Modeled as a continuous variable except race, 4df p-value for RACE Marital status was not associated with any hormones (all P>0.25). Compared to non-Hispanic white women, non-Hispanic black women had 13.491 nmol/l (95% CI=-24.806, -2.176) higher baseline of SHBG and Hispanic women had 11.621 nmol/l (95% CI=-19.154, -4.089) higher baseline SHBG. Race was not associated with the other hormones (P>0.18, Table 5). Associations between Hormone Levels, Global Cognition and Cognitive Factors, Baseline Associations: Associations of baseline levels of cognitive variables with baseline levels of hormone levels used linear regression models; results are presented in Table 6. Age was included as a confounder in the models correlating baseline global cognition or baseline verbal memory with SHBG because they changed a cognition-hormone 23 association beta coefficient by more than 10%; formal education was included in the models correlating verbal memory or executive functions with estrone. There were no significant associations between any baseline hormone levels and any cognitive functions; the positive associations of baseline total testosterone with baseline global cognition and baseline verbal memory were of borderline significance (p=0.06; Table 6). Associations between Hormone Levels, Global Cognition and Cognitive Factors: Association with Cognitive Change: Change in cognitive function was assessed after a 2.5-year follow-up period. Age and formal education were included as confounders in some models as shown in Table 7. Consistent with the association of baseline hormones with baseline cognition (Table 6), there were no significant associations between hormone levels and change in global cognition or other cognitive functions; the inverse association of average estradiol with change in executive functions was of borderline significance (p=0.08; Table 7). According to histogram plots of residuals, residual-predicted value and residual-each independent variables, we conclude that the normality, linearity and homogeneity were met 24 Table 5.Association Between Demographic Variables and Hormone levels Demogra phic Variable Value Coefficients 1 df P value 95% CI for P a value STD Lower Bound Upper Bound Dependent Variable: Total Testosterone , N=267 Age 3.585 1.090 0.001 1.439 5.732 Formal Education high school or less -3.412 35.111 0.92 -72.545 65.721 . Some college 13.447 16.468 0.41 -18.979 45.873 College graduate (referent) 0.62 Employ Not employed (referent) 0.044 Employed 31.077 15.389 0.04 0.777 61.377 Marital Status Married (referent) - - - - - 0.25 Never married -8.595 27.548 0.75 -62.836 45.647 . Separated 17.842 17.024 0.29 -15.678 51.361 Race White, non-Hispanic (referent) 0.26 Black, non-Hispanic 24.689 33.817 0.46 -41.899 91.277 Hispanic -10.208 21.276 0.63 -52.102 31.686 Asian -50.197 24.222 0.039 -97.890 -2.503 Other -1.879 39.049 0.96 -78.768 75.010 Dependent variable: Free Testosterone, N=266 Age 0.019 0.018 0.27 -0.015 0.054 Formal Education high school or less 0.183 0.555 0.74 -0.909 1.275 . Some college 0.414 0.260 0.11 -0.099 0.927 College graduate (referent) 0.20 Employ Not employed (referent) 0.18 Employed 0.332 0.245 0.18 -0.151 0.815 Marital Status Married, marital situation (referent) 0.59 Never married -0.159 0.437 0.72 -1.020 0.702 . Separated 0.089 0.271 0.74 -0.445 0.624 Race White, non-Hispanic (referent) 0.17 Black, non-Hispanic 0.650 0.552 0.24 -0.437 1.737 Hispanic 0.201 0.336 0.55 -0.461 0.864 Asian -0.663 0.383 0.08 -1.417 0.091 Other 0.570 0.617 0.36 -0.646 1.786 Dependent variable: Progesterone, N=307 Age -0.507 0.283 0.075 -1.065 0.051 Formal Education high school or less -0.864 9.452 0.93 -19.464 17.736 . Some college -6.204 4.258 0.15 -14.584 2.175 College graduate (referent) 0.28 25 Employ Not employed (referent) 0.064 Employed -7.500 4.028 0.064 -15.427 0.427 Marital Status Married, marital situation (referent) 0.27 Never married 0.137 7.063 0.98 -13.762 14.036 . Separated -5.251 4.375 0.23 -13.860 3.359 Race White, non-Hispanic (referent) 0.59 Black, non-Hispanic -10.045 8.485 0.24 -26.741 6.651 Hispanic -5.851 5.648 0.30 -16.965 5.264 Asian 3.160 6.408 0.62 -9.451 15.771 Other -2.080 10.497 0.84 -22.735 18.576 Dependent variable: Estradiol, N=306 Age -0.043 0.028 0.12 -0.098 0.012 Formal Education high school or less 0.732 0.930 0.43 -1.099 2.563 . Some college 0.537 0.420 0.20 -0.288 1.363 College graduate (referent) 0.17 Employ not employed (referent) 0.90 Employed -0.050 0.399 0.90 -0.836 0.736 Marital Status Married, marital situation (referent) 0.91 Never married -0.002 0.697 0.99 -1.373 1.370 . Separated -0.053 0.432 0.90 -0.904 0.797 Race White, non-Hispanic (referent) 0.013 Black, non-Hispanic 1.851 0.822 0.025 0.235 3.468 Hispanic 1.067 0.547 0.052 -0.010 2.143 Asian -0.693 0.621 0.26 -1.914 0.529 Other 1.690 1.016 0.097 -0.310 3.690 Dependent variable: Estrone, N=306 Age 0.008 0.095 0.94 -0.178 0.194 Formal Education high school or less 3.717 3.102 0.23 -2.387 9.820 . Some college 3.773 1.398 0.007 1.021 6.524 College graduate (referent) 0.009 Employ not employed (referent) 0.18 Employed 1.797 1.340 0.18 -0.840 4.435 Marital Status Married, marital situation (referent) 0.59 Never married 0.757 2.343 0.75 -3.853 5.368 . Separated 1.207 1.452 0.41 -1.650 4.065 Race White, non-Hispanic (referent) 0.11 Black, non-Hispanic 5.591 2.788 0.046 0.105 11.077 Hispanic 1.865 1.856 0.32 -1.788 5.518 Asian -2.470 2.106 0.24 -6.614 1.675 Other 3.211 3.448 0.35 -3.575 9.997 26 Dependent variable: Prolactin, N=294 Age -0.012 0.021 0.57 -0.053 0.029 Formal Education high school or less -0.298 0.700 0.67 -1.676 1.080 Some college -0.537 0.311 0.086 -1.149 0.076 College graduate (referent) 0.14 Employ not employed (referent) 0.008 Employed -0.782 0.293 0.008 -1.359 -0.205 Marital Status Married, marital situation (referent) 0.49 Never married -0.015 0.516 0.98 -1.031 1.001 . Separated -0.250 0.322 0.44 -0.884 0.385 Race White, non-Hispanic (referent) 0.12 Black, non-Hispanic -0.699 0.637 0.27 -1.953 0.554 Hispanic -0.045 0.411 0.91 -0.853 0.764 Asian 0.888 0.458 0.054 -0.014 1.789 Other -0.893 0.748 0.23 -2.366 0.580 Dependent variable: Baseline of SHBG, N=307 Age 0.835 0.191 <0.001 0.459 1.211 Formal Education high school or less -2.385 6.526 0.71 -15.228 10.457 . Some college -5.050 2.940 0.09 -10.835 0.736 College graduate (referent) 0.15 Employ not employed (referent) 0.14 Employed 4.086 2.791 0.14 -1.406 9.579 Marital Status Married, marital situation (referent) 0.87 Never married 0.393 4.895 0.94 -9.240 10.026 . Separated -0.350 3.032 0.91 -6.317 5.617 Race White, non-Hispanic (referent) 0.005 Black, non-Hispanic -13.491 5.750 0.02 -24.806 -2.176 Hispanic -11.621 3.828 0.003 -19.154 -4.089 Asian -6.178 4.343 0.15 -14.725 2.368 Other -12.801 7.114 0.07 -26.799 1.198 Dependent variable: Average of Change in SHBG, N=278 Age -0.070 0.078 0.37 -0.224 0.083 Formal Education high school or less 0.419 2.400 0.86 -4.307 5.144 . Some college 0.282 1.141 0.80 -1.963 2.528 College graduate (referent) 0.78 Employ not employed (referent) 0.10 Employed -1.739 1.068 0.10 -3.842 0.365 Marital Status Married, marital situation (referent) 0.52 Never married 4.136 1.896 0.030 0.403 7.869 Separated 1.024 1.159 0.38 -1.258 3.307 27 Race White, non-Hispanic (referent) 0.20 Black, non-Hispanic 3.347 2.249 0.14 -1.080 7.775 Hispanic 2.940 1.469 0.046 0.047 5.832 Asian 0.161 1.661 0.92 -3.109 3.431 Other -1.014 2.751 0.71 -6.429 4.402 Beta estimates are from linear regression models, with averaged hormone variables as the dependent variable. a. Modeled as a continuous variable except race, 4df p-value for RACE result from one-way ANOVA. 28 Table 6. Association of Baseline Hormones with Baseline Cognition Hormone, N Standardized Coefficients P value 95% CI for STD Lower Bound Upper Bound Dependent Variable: Baseline Global Cognition Baseline SHBG a , N=307 0.005 0.004 0.22 -0.003 0.013 Baseline Proclactin, N=294 0.032 0.041 0.43 -0.048 0.113 Baseline Progesterone, N=307 0.001 0.003 0.73 -0.004 0.006 Baseline Estradiol, N=306 -0.000 0.003 0.94 -0.006 0.006 Baseline Estrone, N=306 0.001 0.005 0.87 -0.009 0.011 Baseline Free Testosterone, N=266 0.037 0.043 0.40 -0.049 0.122 Baseline Total Testosterone, N=267 0.001 0.001 0.061 # -0.000 0.003 Dependent variable: Baseline Verbal Memory Baseline SHBG a , N=307 0.005 0.003 0.10 -0.001 0.011 Baseline Proclactin, N=294 0.036 0.032 0.26 -0.027 0.100 Baseline Progesterone, N=307 0.001 0.002 0.56 -0.003 0.005 Baseline Estradiol, N=306 0.002 0.002 0.51 -0.003 0.006 Baseline Estrone, N=306 0.001 0.004 0.73 -0.007 0.009 Baseline Free Testosterone, N=266 0.046 0.034 0.18 -0.022 0.114 Baseline Total Testosterone, N=267 0.001 0.001 0.060 # -0.000 0.002 Dependent variable: Baseline Executive Functions Baseline SHBG a , N=307 0.004 0.003 0.19 -0.002 0.010 Baseline Proclactin, N=294 0.027 0.030 0.38 -0.033 0.087 Baseline Progesterone, N=307 0.001 0.002 0.69 -0.003 0.005 Baseline Estradiol, N=306 -0.002 0.002 0.42 -0.006 0.003 Baseline Estrone, N=306 -0.001 0.004 0.90 -0.008 0.007 Baseline Free Testosterone, N=266 0.008 0.032 0.80 -0.056 0.072 Baseline Total Testosterone, N=267 0.001 0.001 0.37 -0.001 0.002 a adjusted for age. b adjusted for formal education. *probability p≤0.05; # 0.05<p≤0.1. 29 Table 7. Association between Hormones and 2.5-Year Change in Cognitive Functions Hormone, N Standardized Coefficients P value 95% CI for STD Lowe r Boun d Upper Bound Dependent Variable: Change in Global Cognition Baseline of SHBG a , N=307 0.0017 0.0025 0.49 -0.003 0.007 Change of SHBG over trial, N=278 0.005 0.007 0.47 -0.009 0.019 Averaged Proclactin, N=294 -0.012 0.025 0.62 -0.062 0.037 Averaged Progesterone, N=307 0.002 0.002 0.18 -0.001 0.006 Averaged Estradiol, N=306 0.008 0.018 0.65 -0.027 0.043 Averaged Estrone, N=306 -0.001 0.005 0.97 -0.011 0.010 Averaged Free Testosterone, N=266 -0.012 0.033 0.72 -0.078 0.054 Averaged Total Testosterone a , N=267 -0.001 0.0005 0.95 -0.001 0.001 Dependent variable: Change in Verbal Memory Baseline of SHBG a , N=307 0.003 0.003 0.27 -0.002 0.009 Change of SHBG over trial, N=278 -0.005 0.008 0.53 -0.020 0.011 Averaged Proclactin, N=294 -0.008 0.027 0.77 -0.061 0.045 Averaged Progesterone, N=307 0.002 0.002 0.27 -0.002 0.006 Averaged Estradiol, N=306 0.011 0.019 0.57 -0.027 0.048 Averaged Estrone b , N=306 0.005 0.006 0.39 -0.006 0.016 Averaged Free Testosterone, N=266 0.016 0.036 0.66 -0.055 0.086 Averaged Total Testosterone, N=267 0.001 0.001 0.79 -0.001 0.001 Dependent variable: Change in Executive Functions Baseline of SHBG, N=307 0.002 0.002 0.39 -0.002 0.005 Change of SHBG over trial, N=278 -0.005 0.004 0.30 -0.013 0.004 Averaged Proclactin, N=294 0.004 0.017 0.81 -0.030 0.038 Averaged Progesterone, N=307 0.001 0.001 0.70 -0.002 0.003 Averaged Estradiol, N=306 -0.021 0.012 0.08 # -0.045 0.003 Averaged Estrone b , N=306 -0.001 0.004 0.78 -0.008 0.006 Averaged Free Testosterone, N=266 -0.012 0.020 0.54 -0.052 0.028 Averaged Total Testosterone, N=267 -0.001 0.000 0.56 -0.001 0.000 a adjusted for age. b adjusted for formal education. Models have change in global cognition or cognitive factors as dependent variables and adjust for its own baseline level. *probability p≤0.05; # 0.05<p≤0.1. 30 DISCUSSION In the Women’s Isoflavone Soy Health (WISH) trial, we examined associations between sex hormones (including prolactin, progesterone, estradiol, estrone, free testosterone and total testosterone) and SHBG with two domains of cognitive functions and global cognition. In the cross-sectional analyses, there were no significant associations between any baseline hormone levels and any baseline cognitive factors or baseline global cognition. The lack of associations was also observed in analyses of hormone levels with cognitive change in longitudinal analyses. Only trends between baseline total testosterone and baseline global cognition (P=0.061, Table 6) or baseline verbal memory (P=0.060, Table 6) were found; longitudinal analyses of cognitive change did not support these cross-sectional associations. In longitudinal analyses, a trend between estradiol and executive functions was found (P=0.08, Table 7). Although some studies have reported significant associations between estrone or estradiol and specific cognitive measures, in either beneficial (Ryan J et al., 2012; Lebrun CE., 2005; Yaffe K., 2007) or deleterious (Yaffe K., 1998; Laughlin GA., 2010) directions, findings in most studies (Ryan J et al., 2012; Lebrun CE., 2005; Yaffe K., 2007; Yaffe K., 1998; Laughlin GA., 2010; Paganini-Hill A et al., 1996; Barrett-Connor E, Goodman-Gruen 31 D., 1999; Henderson VW et al., 2003; den Heijer T, et al., 2003; Almeida OP et al., 2005; Herlitz A et al., 2007; Luetters C, et al., 2007) are consistent with our null results. Total testosterone levels have been linked to better global cognition (Barrett-Connor E, Goodman-Gruen D., 1999) and poorer verbal fluency (Thilers PP et al., 2006) in postmenopausal women, while no associations between free testosterone and cognitive outcomes were found. As a carrier protein for estradiol and testosterone, SHBG is important in the hormone uptake into neurons (Caldwell JD et al., 2009). Similar to our WISH population, other studies in postmenopausal women report no association of SHBG with cognitive abilities (Ryan J et al., 2012; Paganini-Hill A et al., 1996). Serum progesterone was negatively associated with performance on a clock drawing task (Paganini-Hill A et al., 1996) and unrelated to several cognitive end points in smaller studies (Drake EB, et al., 2000). Henderson, V.W., et al., 2013 found serum progesterone was positively associated with verbal memory and global cognition in postmenopausal women. We did not find such associations in our sample of postmenopausal women. CONCLUSION In this sample of healthy postmenopausal women, we failed to support the hypothesis that sex hormone levels as measured by serum concentrations 32 are related to verbal memory, executive functions or global cognition. Similarly, the cumulative exposures of hormone levels are not related to change in cognitive factors or global cognition over an average 2.7-year period. Somewhat consistent with prior analyses, the WISH sample showed borderline and positive associations (P=0.061) between total testosterone and global cognition, and between testosterone and verbal memory (P=0.060). In addition, estradiol showed a negative association with change in executive functions (P=0.08). There are limitations to these findings. Sex hormone and SHBG can be synthesized within the CNS, and blood levels may imprecisely reflect concentrations in the brain (Hojo Y , et al., 2008; Schumacher M, et al., 2007; Wang YM, et al., 1990; Herbert Z, et al., 2005). Cognitive functions may also be affected by environmental and lifestyle factors that were not considered in these analyses. Our results also do not apply to men or women of reproductive age, as our analytic population did not include these groups. 33 REFERENCES Almeida OP, Lautenschlager N, Vasikaram S, Leedman P, Flicker L (2005) Association between physiological serum concentration of estrogen and the mental health of community-dwelling postmenopausal women age 70 years and over. Am J Geriatr Psychiatry 13(2):142–149. Barrett-Connor E, Goodman-Gruen D (1999) Cognitive function and endogenous sex hormones in older women. J Am Geriatr Soc 47(11):1289–1293. Caldwell JD, Jirikowski GF (2009) Sex hormone binding globulin and aging. Horm Metab Res 41(3):173–182. 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(2012) Hormone levels and cognitive function in postmenopausal midlife women. Neurobiol Aging 33(7):1138–1147. Rubinow, D. R., and Schmidt, P. J. (1996). Androgens, brain, and behavior. Am. J. Psych. 153, 974–984. Ryan, J., Stanczky, F.Z., Dennerstein, L., Mack, W.J., Clark, M.S., Szoeke, C., Kildea, D., Henderson, V.W., 2010. Hormone levels and cognitive function in postmenopausal midlife women. Neurobiol. Aging [Epub ahead of print]. Schumacher M, et al. (2007) Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 28(4): 387–439. Sherwin, B. B., and Tulandi, T. (1996). “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri [see comments]. J. Clin. Endocrinol. Metabol. 81, 2545–2549. Sherwin, B. B. (1988). Estrogen and/or androgen replacement therapy and 38 cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13, 345–357. Simon, J.A., Reape, K.Z., 2009. Understanding the menopausal experience of professional women. Menopause 16, 73–76. Henderson, V.W., Dudley, E.C., Guthrie, J.R., Burger, H.G., Dennerstein, L., 2003. Estrogen exposures and memory at midlife: a population-based study of women. Neurology 60, 1369–1371. Sternbach, H. (1998). Age-associated testosterone decline in men: clinical issues for psychiatry. Am. J. Psych. 155, 1310–1318. Thilers PP, Macdonald SW, Herlitz A (2006) The association between endogenous free testosterone and cognitive performance: A population-based study in 35 to 90 yearold men and women. Psychoneuroendocrinology 31(5):565–576. US Bureau of the Census Population Reports, Series P-25, No. 1018, Projections of the Population of the United States, by Age, Sex, and Race: 1988 to 2080, by Gregory Spencer. Washington, DC: US Government Printing Office; 1989. Wang YM, Bayliss DA, Millhorn DE, Petrusz P, Joseph DR (1990) The androgen-binding protein gene is expressed in male and female rat brain. Endocrinology 127(6): 3124–3130. Yaffe K, et al. (2007) Endogenous sex hormone levels and risk of cognitive 39 decline in an older biracial cohort. Neurobiol Aging 28(2):171–178. Yaffe, K., Grady, D., Pressman, A., and Cummings, S. (1998). Serum estrogen levels, cognitive performance, and risk of cognitive decline in older community women. J. Am. Geriatrics Soc. 46, 816–821. Yaffe, K., Browner, W., Cauley, J., Launer, L., and Harris, T. (1999). Association between bone mineral density and cognitive decline in older women. J. Am. Geriatrics Soc. 47, 1176–1182. APPENDIX Table A: Tests used to assess cognition Executive/expressive/visuospatial factor Symbol Digit Modalities Test Trail Making Test, Part B Shipley Abstraction Letter-Number Sequencing Block Design Judgment of Line Orientation Category Fluency Boston Naming Test Verbal episodic memory (list learning) factor California Verbal Learning Test, immediate recall California Verbal Learning Test, delayed recall Verbal episodic memory (logical memory) factor East Boston Memory Test, immediate recall East Boston Memory Test, delayed recall Visual episodic memory factor Faces I, immediate recall Faces II, delayed recall
Abstract (if available)
Abstract
Objective: The purpose of this study was to assess the association between endogenous levels of hormones and changes in cognitive function measured over 2.5 years among postmenopausal women. ❧ Methods: The Women’s Isoflavone Soy Health (WISH) trial was a randomized, double-blind and placebo-controlled trial. A total of 350 postmenopausal women were randomized to isoflavone soy protein (ISP) or placebo groups and followed on their randomized intervention for 30 months. The panel of fasting plasma levels of sex steroid hormones included progesterone (pg/ml), estradiol (pg/ml), estrone (pg/ml), prolactin (ng/ml), total testosterone (pg/ml) and free testosterone (pg/ml). Sex hormone binding globulin (SHBG, nmol/L) was also measured. Neuropsychological tests were selected to measure a broad spectrum of cognitive abilities. Participants were tested before randomized intervention and at the study endpoint, approximately 2.5 years later. Changes in cognition were summarized as endpoint values minus baseline values. Associations of changes in cognitive function were evaluated with endogenous levels of hormones using multiple linear regression models. Associations of baseline levels of cognitive variables with baseline levels of hormone levels used linear regression models, adjusting for age and education. Evaluation of collinearity, correlation structure and model assumptions were performed to ensure model validity. ❧ Result: There were no significant associations between any baseline hormone levels and any cognitive functions
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Association between endogenous sex hormone levels and cognition: the Women’s Isoflavone Soy Health (WISH) trial
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