MENOPAUSE A randomized trial of the effect of testosterone and estrogen on verbal fluency, verbal memory, and spatial ability in healthy postmenopausal women Ljiljana Kocoska-Maras, M.D., a Niklas Zethraeus, Ph.D., b,c Angelique Fl oter Rådestad, M.D., Ph.D., a Tore Ellingsen, Ph.D., b Bo von Schoultz, M.D., Ph.D., a Magnus Johannesson, Ph.D., b and Angelica Linden Hirschberg, M.D., Ph.D. a a Department of Women s and Children s Health, Division of Obstetrics and Gynecology, Karolinska Institutet; b Department of Economics, Stockholm School of Economics; and c Medical Management Centre, Institution for Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden Objective: To test the causal relationship between sex hormones and cognitive skills in postmenopausal women. We hypothesized that testosterone would decrease verbal memory and verbal fluency and increase spatial ability compared with a placebo. For estrogen, we conversely hypothesized that the treatment would increase verbal fluency and verbal memory and decrease spatial ability. Design: Randomized, double-blind, placebo-controlled, parallel-group trial. Setting: Women s health clinical research unit at a university hospital. Patient(s): Two-hundred healthy, naturally postmenopausal women aged 50 65 years. Intervention(s): Randomization to 4 weeks treatment with testosterone (testosterone undecanoate, 40 mg/day), estrogen (oral E 2 2 mg/day) or placebo. Main Outcome Measure(s): Comparisons in verbal fluency, verbal memory, and spatial ability between the three treatment groups. Result(s): We found no significant effects of testosterone or estrogen on verbal fluency, verbal memory, or spatial ability. Conclusion(s): Our results give no support for short-term testosterone or estrogen treatment having any substantial effect on verbal fluency, verbal memory, or spatial ability in healthy postmenopausal women. (Fertil Steril Ò 2011;95:152 7. Ó2011 by American Society for Reproductive Medicine.) Key Words: Estrogen, testosterone, memory, spatial ability, cognition, randomized trial The brain is an important target organ for sex steroids. Estrogen and testosterone act via genomic mechanisms by binding to their specific receptors, modulating the synthesis, release, and metabolism of several neurotransmitters (1 2). Sex hormones also influence brain functions via more rapid, nongenomic mechanisms influencing the electrical excitability of neuron activity (3). Several studies have found a correlation between estrogen and cognitive abilities (4 6). Menstrual cycle studies have shown that women improve verbal abilities in menstrual phases associated Received April 7, 2010; revised May 26, 2010; accepted May 27, 2010; published online July 29, 2010. Supported by the Swedish Research Council (No. 20324), Karolinska Institutet, Jan Wallander and Tom Hedelius Foundation, and the Swedish Council for Working Life and Social Research. L. K-M. has nothing to disclose. N.Z. has nothing to disclose. A.F.R. has nothing to disclose. T.E. has nothing to disclose. B.v.S. has nothing to disclose. M.J. has nothing to disclose. A.L.H. has nothing to disclose. Reprint requests: Angelica Linden Hirschberg, M.D., Ph.D., Department of Women s and Children s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, SE-171 76 Stockholm, Sweden (FAX: 46-8-5177-4252; E-mail: angelica.linden-hirschberg@ karolinska.se). with high estrogen levels, and spatial abilities in menstrual phases associated with low estrogen levels (6 11). These results are contrasted by some studies that did not find differences in cognitive performance between phases of the menstrual cycle (12 13). In addition, Herlitz et al. (14) did not find any differences in cognitive performance between groups of premenopausal, perimenopausal, and postmenopausal women with different estrogen status. However, a recent large longitudinal study showed a decrease in verbal memory during menopause transition from premenopause to perimenopause (15). Other studies have evaluated the effect of hormone therapy (HT) on cognitive performance. Several observational studies suggest that HT with estrogen improves verbal memory and fluency in healthy postmenopausal women (16 18). These results contrast with findings in the large randomized Women s Health Initiative Memory Study (WHIMS), which reports that estrogen in combination with progestin do not improve global cognitive function measured by the Modified Mini-Mental State Examination compared with placebo in postmenopausal women 65 years or older (19), whereas estrogen alone could have adverse effects on global cognitive function in women of the same age (20). Furthermore, a substudy from WHIMS showed that combined HT decreased verbal memory (21), whereas 152 Fertility and Sterility â Vol. 95, No. 1, January 2011 0015-0282/$36.00 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2010.05.062
estrogen only was associated with lower spatial ability in older postmenopausal women (22). However, in younger postmenopausal women, randomized clinical trials lend support for a beneficial effect of estrogen on cognitive function (23 25). The results may support the notion that there is a protective effect of estrogen on cognition when the therapy is initiated early after menopause, but an adverse effect in older women (26 27). For men there is some evidence from randomized studies that testosterone may improve spatial ability and memory, but the results are not conclusive (28). For women, little is known about the effects of testosterone on cognitive performance, and there is a lack of carefully controlled randomized studies (29). Thilers et al. (30) found that endogenous testosterone was negatively correlated with verbal fluency in women, and some studies indicate a positive relationship between testosterone and visuospatial ability across the menstrual cycle (8, 31). Two small sample studies also found an increase in visuospatial ability (32) and object location memory (33) in younger women after a single dose of testosterone. In contrast, Miller et al. (34) found no effects of testosterone replacement on cognitive function in women with hypopituitarism. Current evidence is ambiguous and insufficient to draw strong conclusions about the causal relationship between sex hormones and cognitive skills in women. We performed a double-blind, placebo-controlled trial with postmenopausal women randomly allocated to testosterone, estrogen, and placebo and previously reported effects on economic behavior (35). We tested the causal relationship between hormones and cognitive abilities and hypothesized that testosterone would decrease verbal memory and fluency and increase spatial ability compared to placebo. For estrogen, we conversely hypothesized that the treatment would increase verbal fluency and memory and decrease spatial ability. MATERIALS AND METHODS The study was approved by the local ethics committee in Stockholm (2006/ 481-31/3) and the Swedish Medical Products Agency (151:2006/29773), and all women gave their written consent to participate in the study. Inclusion and Exclusion Criteria Healthy, naturally postmenopausal women aged 50 65 years with body mass index of 19 30 were recruited into the study. Postmenopausal status was defined as last menstrual bleeding at least 12 months before the study or serum levels of FSH greater than 30 IU/L. Exclusion criteria were smoking, hypertension, hyperlipidemia, or other cardiovascular disease, risk factors for thromboembolism, diabetes, and history of cancer. Women with obvious difficulties in speaking or understanding were also excluded. Intake of any sex steroids during the last three months was not allowed. However, wellcontrolled thyroid hormone substitution for treatment of hypothyroidism was permitted. Treatment The study was performed at the Women s Health Research Unit, Karolinska University Hospital, Stockholm, Sweden. Recruitment and screening of women have been described elsewhere (35). Subjects that fulfilled the inclusion criteria were included in the study (n ¼ 203 were randomized; n ¼ 200 completed the study; Fig. 1). Before the start of treatment, a blood sample was taken after an overnight fast. Serum was separated by centrifugation and then stored at 70 C for later analyses of sex hormones. Each subject was randomized to estrogen (E 2, 2 mg/d), testosterone (T undecanoate 40 mg/d) or placebo treatment for a period of 4 weeks. These hormone doses have well-documented clinical effects (36 37). The randomization was performed with blocks of four and 12 subjects in each block. At the end of the treatment period, a new blood sample was taken after an overnight fast. After receiving breakfast at the clinic, each woman (in groups of 1 6 individuals) participated in a 30-minute session with economic experiments (35). After a short break (approximately 30 minutes) all women completed the cognitive test session (approximately 45 minutes). All cognitive test sessions in the study were conducted by the same person and between 9:30 and 10:15 AM. Laboratory Tests Serum concentrations of total T and E 2 were determined by radioimmunoassay using commercial kits and serum concentrations of sex hormone-binding globulin and FSH were determined by chemiluminescent enzyme immunometric assays, as previously described (35). Apparent concentrations of free T were calculated from values of total T, sex hormone-binding globulin, and a fixed albumin concentration of 40 g/l by successive approximation, using a computer program based on an equation system derived from the law of mass action (38). Cognitive Ability Tests In the verbal fluency test, each woman was asked to write as many words as possible beginning with a specified letter during 1 minute (39). The letters were F, A, S, and N, each on a separate piece of paper and one at a time. The sum of words generated from the four letters was taken as measure of verbal fluency. In the test of episodic verbal memory, a list of 12 common unrelated nouns were presented verbally with the instruction to remember as many of the FIGURE 1 The design of the double-blind randomized trial. Estrogen (n = 66; 2 dropouts) 240 assessed for eligibility (37 excluded) 203 Randomized Testosterone (n = 67) Placebo (n = 67; 1 dropout) Study design - Randomized - Double-blind Study subjects - Healthy women - Postmenopausal - Age 50-65 years Treatment alternatives - Estradiol 2 mg daily - Testosterone undecanoate 40 mg daily - Placebo - 4 weeks treatment duration Cognitive test session - At treatment cessation - Performed between 09.30-10.15 in the morning Fertility and Sterility â 153
words as possible for an immediate free recall test (40). Four lists were presented one at a time. The sum of nouns remembered from the four lists (range, 0 48) was taken as measure of verbal memory. Spatial ability was measured by using a mental rotation test developed by Vandenberg and Kuse (41) based on Shephard and Metzler (42). The test is a paper-and-pencil test containing 20 items. In each item the woman is instructed to select two figures from four alternatives that are rotated versions of the target figure to the left. Two points are given for a correct answer on two, one point for selecting one correct and zero otherwise. The time limit is 10 minutes. The score on the mental rotation test (range, 0 40) was taken as measure of spatial ability. Statistical Tests Categorical data were summarized using frequency counts and percentages. Normally distributed data are presented as arithmetic mean and standard deviation (SD), otherwise as median and quartile range (Q 25 Q 75 ). Differences between treatment groups were analyzed using one-way analysis of variance (ANOVA) and one-way analysis of covariance (ANCOVA) with age as the covariate. The estimates from the analyses were presented as mean differences between treatment groups, adjusted and unadjusted for age, with 95% confidence intervals (CIs). Based on the means, SDs, and sample size (3 67) in our sample, we have estimated the smallest clinical differences to be detected in each outcome variables with 80% power when the significance level is 0.05. The results from these calculations were 10% for verbal memory, 11% for verbal fluency, and 30% for spatial ability. Kruskal-Wallis ANOVA by ranks followed by multiple comparisons between treatment groups was performed for hormone data. P < 0.05 was considered statistically significant. RESULTS Baseline characteristics of the naturally postmenopausal women in the three treatment groups are listed in Table 1. The groups were comparable in regard to time since menopause, past use of HT, duration and time since stop of HT, higher education, serum concentrations of E 2, T and free T. However, there was a small but significant difference in age between women in the estrogen group and the placebo group (P<0.05). As previously reported (35), serum concentrations of T increased significantly after 4 weeks of treatment compared with placebo and estrogen treatment (P<0.001 and P<0.001, respectively). In the testosterone group, the mean total T level was 4.4-fold higher than the baseline level after 4 weeks of treatment (2.31 1.85 vs. 0.52 0.31 nmol/l), and the mean free T level was 5.5-fold higher (40.0 35.0 vs. 7.2 5.3 pmol/l). Serum concentrations of E 2 also increased significantly after 4 weeks of treatment compared with placebo and testosterone treatment (P<0.001 and P<0.001, respectively) (35). In the estrogen group, the E 2 level increased by a factor of 7.9 after 4 weeks of treatment compared with baseline (227.0 105.3 vs. 28.6 40.5 pmol/l). There were no significant differences between the three treatment groups in verbal fluency, verbal memory, or spatial ability (P>0.05, respectively; Fig. 2; Table 2). When data were adjusted for age, there were still no significant differences between any of the three treatment groups (ANCOVA, P>0.05 for all comparisons; Table 2). We also tested whether time since menopause or past use of HT influenced the outcomes, and we found no significant differences in verbal or spatial ability between the groups (data not shown). DISCUSSION This randomized, double-blind and placebo-controlled trial demonstrates no significant effects of 4 weeks of treatment with testosterone or estrogen on verbal memory, verbal fluency, or spatial ability in healthy naturally postmenopausal women. HT, resulting in similar serum levels of sex hormones as in the present study, has shown important clinical effects. Estrogen is the most effective treatment for alleviation of menopausal symptoms of flushing, sweating, and sleep disturbance (43). Estrogen is also used for the prevention of osteoporosis and treatment of vaginal dryness and dyspareunia (43). Testosterone therapy of this kind has been shown to improve psychosexual function and well-being in postmenopausal women having hypoactive sexual desire disorder (37, 44, 45). Still, we failed to find any support for our hypothesis that sex hormones affect cognitive performance. This study has considerable statistical power to detect significant differences, especially in verbal fluency and verbal memory. The point estimates of differences in cognitive performance between the groups are also small, and often not consistent with our prior hypotheses; this further strengthens the conclusion that the lack of significant differences is not due to a lack of statistical power. To avoid repeated testing, we did not perform evaluations of cognitive TABLE 1 Baseline characteristics of postmenopausal women treated with testosterone, estrogen, or placebo (mean ± SD or median and quartile range [Q 25 Q 75 ]). Background variables Testosterone (n [ 67) Estrogen (n [ 66) Placebo (n [ 67) Age (y) 58.3 4.2 59.7 3.7 58.1 4.0 Time since menopause (y) 7.4 4.2 8.7 4.3 7.5 4.2 Past hormone use (proportion yes) 0.63 0.58 0.49 Duration of HT (y) 2.5 (1.0 5.0) 3.0 (1.0 8.0) 2.0 (1.0 5.5) Time since end of HT (y) 3.5 (2.0 6.0) 4.0 (2.0 6.0) 3.2 (1.0 5.0) Higher education (proportion having 0.71 0.63 0.62 at least university or college level) E 2 (pmol/l) 22.1 (14.2 35.8) 21.8 (16.2 28.4) 22.4 (11.3 31.2) T (nmol/l) 0.52 (0.22 0.75) 0.48 (0.26 0.77) 0.41 (0.26 0.68) Free T (pmol/l) 6.6 (3.6 9.8) 6.8 (3.5 11.4) 5.8 (4.1 9.7) 154 Kocoska-Maras et al. Effects of sex hormones on cognition Vol. 95, No. 1, January 2011
FIGURE 2 Mean values of verbal fluency, verbal memory, and spatial ability after 4 weeks of treatments with testosterone (T), estrogen (E), and placebo (P). Error bars indicate 95% confidence intervals. There were no significant differences between any of the treatment groups (ANOVA/ANCOVA, P>0.05). 70 60 T E P 50 Test scores 40 30 20 10 0 Verbal fluency Verbal memory Spatial ability function at baseline, and thus we are not able to measure within group differences in test scores. However, because this is a randomized study, we can assume that cognitive function was comparable between groups at baseline. Investigations of HT and cognition in postmenopausal women have yielded inconsistent results. The majority of observational studies (16 18), as well as randomized clinical trials in younger postmenopausal women (<65 years old), have suggested beneficial effects of estrogen (23 25). However, large long-term randomized clinical trials in older postmenopausal women (i.e., R65 years old) have failed to demonstrate improvements in cognitive function, and some have even shown harmful effects (19 22, 46). It has been suggested that the diverse effects could be due to different age at initiation of treatment, time since menopause, and type of regimen that is, estrogen only or combined estrogen-progestin therapy (26, 27). This study used a relatively young cohort of postmenopausal women who experienced natural menopause 7 8 years earlier. Most previous clinical trial data on younger postmenopausal women have been on those with surgical menopause (26, 27). Our results were not significantly influenced by age, time since menopause, or prior use of HT. Furthermore, few women (n ¼ 3) had vasomotor symptoms that could interfere with cognitive function. Recently, data from the Study of Women s Health Across the Nation suggested that menopause transition-related cognitive difficulties may be time limited (15). Whereas perimenopause was associated TABLE 2 Mean values and SD of verbal fluency, verbal memory, and spatial ability after 4 weeks of treatments with testosterone (T), estrogen (E), and placebo (P). Cognitive test T E P P value ANOVA ANCOVA a T-P E-P T-E Verbal fluency 58.4 (11.87) 55.3 (14.45) 55.7 (12.74) 0.334 0.372 Verbal memory 24.4 (4.57) 24.9 (5.00) 25.2 (5.46) 0.611 0.553 Spatial ability 9.0 (5.22) 9.4 (5.26) 8.7 (5.84) 0.744 0.453 2.69 ( 1.76; 7.14) 2.73 ( 1.72; 7.18) a 0.40 ( 4.86; 4.07) 0.07 ( 4.60; 4.45) a 3.08 ( 1.38; 7.55) 2.80 ( 1.71; 7.31) a 0.85 ( 2.56; 0.86) 0.30 ( 2.02; 1.42) 0.55 ( 2.27; 1.17) 0.81 ( 2.50; 0.88) a 0.01 ( 1.71; 1.73) a 0.82 ( 2.54; 0.90) a 0.28 ( 1.57; 2.14) 0.72 ( 1.14; 2.59) 0.44 ( 2.30; 1.42) 0.34 ( 1.48; 2.17) a 1 16 ( 0.70; 3.00) a 0.81 ( 2.66; 1.03) a Note: There were no significant differences between any of the treatment groups (estimated mean differences and 95% CI, ANOVA/ANCOVA; P>0.05). a Age adjusted. Fertility and Sterility â 155
with a decrement in cognitive performance, women with a stable postmenopausal status had an improvement and did not differ from younger premenopausal women. There is limited information about androgens and cognitive function in women. One previous small study showed improved cognitive functioning by both estrogen and androgen replacement therapy in surgically menopausal women (23). To our knowledge, this is the first randomized trial of testosterone treatment on verbal and spatial ability in healthy, naturally postmenopausal women. In agreement with a study in androgen-deficient women with hypopituitarism (34), we found no significant effects of testosterone treatment on cognitive function. However, testosterone treatment in women with anorexia nervosa showed improved spatial cognition compared with placebo (47), whereas another small study in women with Turner syndrome showed improved verbal memory but no effect on spatial cognition by testosterone added to estrogen-progestin therapy (48). There are also few data in young healthy women indicating increased visuospatial ability and object location memory after a single dose of testosterone (32, 33). Our investigation was a short-term study, and it can not be excluded that longer treatment could have resulted in other outcomes. However, it is well known that sex hormones may influence brain functions via rapid, nongenomic mechanisms (3). In support of this concept, menstrual cycle studies and shortterm hormone interventions have shown consistent effects on mood and behavior (49, 50). Furthermore, even a single dose of testosterone as mentioned previously has demonstrated significant effects on cognition in young women (32, 33). It is therefore not likely that the duration of treatment was too short to detect relevant effects if there were any. It could also be argued that, because most of the women were highly educated, they were unlikely to show benefit of treatment. Considering that the mean result (i.e., score) of the verbal memory test was approximately 25 (maximum, 48) and the mean result of the spatial ability test was approximately 9 (maximum, 40), no ceiling effects appear to be the case in this study. These performances are age dependent, and our results are within the normal range of performance score for women of this age (40, 41). Our results give no support for any substantial effect of short-term treatment with estrogen on specific cognitive functions in healthy postmenopausal women. 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