Abstract
Purpose
To determine the dose-dependent effects of testosterone administration on cognition in women with low testosterone levels.
Methods
71 hysterectomized women with or without oophorectomy with total testosterone <31 ng/dl and/or free testosterone <3.5 pg/ml received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly intramuscular injections of placebo, 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks. Total testosterone was measured in serum by LC–MS/MS, and free testosterone levels were measured by equilibrium dialysis. Cognitive function was evaluated using a comprehensive battery of standardized neuropsychological tests at baseline and 24 weeks.
Results
46 women who had baseline and end-of-treatment cognitive function data constituted the analytic sample. The five groups were similar at baseline. Mean on-treatment nadir total testosterone concentrations were 15, 89, 98, 134, and 234 ng/dl in the placebo, 3, 6.25, 12.5, and 25 mg groups, respectively. No significant changes in spatial ability, verbal fluency, verbal memory, or executive function were observed in any treatment arm compared to placebo even after adjustment for baseline cognitive function, age, and education. Multiple regression analysis did not show any significant relation between changes in testosterone concentrations and change in cognitive function scores.
Conclusion
Short-term testosterone administration over a wide range of doses for 24 weeks in women with low testosterone levels was neither associated with improvements nor worsening of cognitive function.
Keywords: Testosterone, Menopause, Cognition, Androgen deficiency
Introduction
There has been an increasing interest in the use of testosterone therapy to improve sexual function and body composition in postmenopausal women. Although testosterone administration has been reported to improve some domains of sexual function and body composition in menopausal women as well as women with antidepressant-induced sexual dysfunction [1–3], the effects of testosterone therapy on cognitive function remain unclear.
Brain is an important target for the action of gonadal hormones as it expresses receptors for both estrogen and testosterone, particularly in regions responsible for memory and higher cognitive function, such as hippocampus. Indeed, observations that men tend to perform better in visuospatial tasks and that women have better verbal memory suggest that sex hormones exert sexually dimorphic effects on different domains of cognition [4]. Several observational studies suggest that estrogen is associated with better cognitive performance in healthy postmenopausal women [5]. However, data from controlled trials of estrogen replacement have not shown benefit [6]; some trials have even reported detrimental effects of estrogen replacement on cognition [7, 8].
Recently, research has focused on evaluating the role of androgens on cognitive function in postmenopausal women. Testosterone is aromatized to estradiol, both in the periphery and in the brain. In addition to its direct effects via the androgen receptor, some effects of testosterone administration might be mediated via its aromatization to estradiol [9]. However, the data on the relation of circulating androgen concentrations and cognitive function are inconsistent across studies. In women with polycystic ovary syndrome (PCOS), higher endogenous serum testosterone levels are associated positively with visuospatial memory and negatively with verbal fluency and verbal memory [10, 11]. Similar findings have been noted in healthy pre- and postmenopausal women [12, 13]. However, these findings have not been confirmed by other studies [14, 15]. Furthermore, only a few studies have prospectively examined the effect of exogenous testosterone administration on cognitive performance in the setting of controlled randomized trials [16].
Recently, we demonstrated that short-term (24-weeks) testosterone administration over a wide range of doses (physiologic and supraphysiologic) to hysterectomized women with low testosterone levels improved several domains of sexual function, body composition, and muscle performance with few androgenic adverse effects [17]. Furthermore, there was no worsening of serum cardiovascular risk markers [18]. However, it remains unknown whether the administration of testosterone over a wide range of doses impacts cognitive function. Hence, we investigated the dose–response relation of testosterone administration, across multiple domains of cognitive function in hysterectomized women with low testosterone levels.
Methods
Study design
The Testosterone Dose response in Surgically Menopausal Women (TDSM) trial was a two-center, parallel group, placebo-controlled, double-blind, randomized trial designed to determine the dose–response effects of testosterone on a range of androgen-dependent outcomes [17]. The trial consisted of a 12-week run-in period of transdermal estradiol administration, a 24-week treatment period, and a 16-week recovery period. The study was approved by the institutional review boards of Boston University Medical Center (BUMC) and Charles Drew University of Medicine and Science (Los Angeles, CA, USA), and all participants provided written informed consent.
Subjects
Healthy women aged 41–62 years without cognitive impairment who had undergone hysterectomy with or without partial or total oophorectomy were recruited. The participants had serum total testosterone concentrations <31 ng/dl or free testosterone concentrations <3.5 pg/ml (less than the median for healthy young women [17]). We included women who had hysterectomy alone or partial oophorectomy if their FSH levels were ≥30 U/l or if they were already receiving estrogen therapy. We excluded women diagnosed with major psychoses or bipolar disorders in the past year and depression in the previous 3 months, and dementia as assessed by the mini-mental status examination. Women with a history of breast, ovarian, endometrial, or cervical cancer, hyperandrogenic disorders, cardiac disease or thromboembolic disorders, and those taking glucocorticoids, androgens, spironolactone, and GnRH agonists were also excluded. Women were required to have a normal Pap smear and mammogram within the last 12 months.
Study interventions and randomization
All eligible women were administered a transdermal estradiol (E2) patch applied twice a week and designed to achieve nominal delivery of 50-μg estradiol daily (Alora, Watson Pharmaceuticals) for a 12-week run-in phase. After run-in, the subjects were randomized in a double-blinded fashion to one of five groups to receive weekly IM injections of placebo, 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks.
Hormone assays
Serum total testosterone levels were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with a sensitivity of 2 ng/dl, free testosterone was measured using equilibrium dialysis with a sensitivity of 0.3 pg/ml, and sex hormone-binding globulin levels were measured using an immunofluorometric assay with a sensitivity of 0.5 nmol/l [17].
Assessment of cognition
The University of Wisconsin (UW) oversaw staff training, data collection, and quality control. All participants were tested by the same psychometrician. Cognitive function was evaluated using a comprehensive battery of standardized neuropsychological tests which included measures of visuospatial ability (Puget Sound Route Learning and Complex Figure tests), verbal memory (Paragraph Recall and Buschke Selective Reminding Test), verbal fluency (Phonemic and Category Fluency) attention, and executive function (Visual Spatial Learning Test, Letter–Number Sequencing, Stroop Color-Word Interference Test, and Trail Making Test B and Mazes). Cognitive test procedures are discussed in detail in the supplementary appendix.
Statistical considerations
The analytic sample consisted of subjects who had baseline and follow-up data on efficacy outcomes. Mean change in outcomes was compared across treatment doses by linear regression incorporating adjustment for baseline cognitive test scores, age, and education. Differences in the responses at each dose category were estimated using treatment contrasts and 95 % confidence intervals. Evidence in favor of an overall dose effect was assessed using a Wald-type (F) significance test of the hypothesis that all groups had equal mean response adjusting for baseline age, level of education, and baseline level of the relevant cognitive function measure. Multiple linear regression analyses were performed to test the association between mean changes in cognitive function scores and changes in serum testosterone concentrations, likewise adjusted for these covariates. Analyses were conducted using R version 2.14.2 (R Foundation for Statistical Computing, Vienna, Austria). While cognitive function was not the primary endpoint of the TDSM trial, analyses described here were sufficiently powered to detect overall effect sizes [19], quantifying overall between-group differences, of 0.52 with 80 % probability.
Results
Flow of participants
Of the 850 women who underwent telephone screening, 218 met eligibility criteria, 85 entered the estrogen run-in-period, 71 were randomized, and 46 who had baseline and end-of-treatment cognitive function data constituted the analytic sample [placebo (n = 8), 3 mg (n = 9), 6.25 mg (n = 10), 12.5 mg (n = 10), or 25 mg (n = 9)].
Baseline characteristics
Baseline characteristics across the five treatment groups are displayed in Table 1. Mean age of women in the analytic sample was 53 years and average BMI 29.7 kg/m2. Participants across the dose groups were comparable in terms of age, race, depression history, mini-mental status exam scores, and BMI. The majority of women had received higher education (defined as having at least a university- or college-level degree). 74 % of the women had undergone bilateral oophorectomy.
Table 1.
Baseline demographic and cognitive characteristics by treatment group (n = 46)
| Dose of testosterone enanthate (mg/week) | Placebo (n = 8) | 3 (n = 9) | 6.25 (n = 10) | 12.5 (n = 10) | 25 (n = 9) |
|---|---|---|---|---|---|
| Demographics | |||||
| Age (year) | 54 ± 5 | 55 ± 4 | 52 ± 5 | 52 ± 6 | 54 ± 3 |
| Race n (%) | |||||
| Black | 5 (63) | 6 (67) | 5 (50) | 3 (30) | 3 (33) |
| White | 3 (38) | 3 (33) | 3 (30) | 4 (40) | 5 (56) |
| Other | 0 (0) | 0 (0) | 2 (20) | 3 (30) | 1 (11) |
| Higher education (proportion having at least college level) | 0.75 | 0.43 | 0.67 | 0.71 | 0.86 |
| Mini-mental examination (score out of 30) | 27 | 29 | 29.2 | 28.3 | 29.6 |
| History of depression (self-report) n | 4 | 2 | 2 | 3 | 3 |
| BMI (kg/m2) | 33 ± 4 | 31 ± 6 | 28 ± 6 | 30 ± 5 | 33 ± 4 |
| Hysterectomy alone n (%) | 3 | 2 | 0 | 1 | 4 |
| Partial oophorectomy n (%) | 1 | 1 | 0 | 0 | 0 |
| Bilateral oophorectomy n (%) | 4 | 6 | 10 | 9 | 9 |
| Baseline blood levels | |||||
| Total testosterone (ng/dl) | |||||
| Screening | 9.3 ± 4 | 13 ± 9 | 20 ± 17 | 11 ± 7 | 15 ± 8 |
| Post-estrogen run-in | 16 ± 10 | 13 ± 5 | 14 ± 14 | 10 ± 6 | 17 ± 9 |
| Free testosterone (pg/ml) | |||||
| Screening | 1.0 ± 0.5 | 1.0 ± 0.9 | 1.1 ± 1.3 | 1.0 ± 0.6 | 1.0 ± 0.7 |
| Post-estrogen run-in | 2.8 ± 2.0 | 2.1 ± 0.7 | 2.2 ± 2.8 | 1.8 ± 0.9 | 2.3 ± 1.1 |
| SHBG (nmol/l) | 68 ± 27 | 71 ± 33 | 58 ± 23 | 56 ± 26 | 93 ± 41 |
| Baseline cognitive function scores | |||||
| Spatial ability tests | |||||
| Route learning test (immediate) | 0.38 ± 0.17 (7) | 0.42 ± 0.07 (7) | 0.56 ± 0.08 (8) | 0.40 ± 0.13 (7) | 0.33 ± 0.16 (9) |
| Route learning test (delayed) | 0.39 ± 0.15 (7) | 0.50 ± 0.10 (7) | 0.53 ± 0.18 (8) | 0.52 ± 0.18 (7) | 0.39 ± 0.21 (9) |
| Complex figure (immediate) | 0.73 ± 0.11 (8) | 0.62 ± 0.12 (8) | 0.61 ± 0.16 (9) | 0.60 ± 0.10 (10) | 0.58 ± 0.23 (8) |
| Complex figure (delayed) | 0.63 ± 0.10 (8) | 0.58 ± 0.16 (8) | 0.56 ± 0.13 (9) | 0.56 ± 0.12 (10) | 0.45 ± 0.30 (8) |
| Verbal memory tests | |||||
| Paragraph (immediate) | 0.52 ± 0.20 (8) | 0.39 ± 0.12 (8) | 0.36 ± 0.19 (9) | 0.31 ± 0.12 (10) | 0.40 ± 0.18 (9) |
| Paragraph (delayed) | 0.42 ± 0.19 (8) | 0.26 ± 0.11 (8) | 0.28 ± 0.19 (9) | 0.27 ± 0.16 (10) | 0.31 ± 0.18 (9) |
| Buschke (immediate: total correct) | 0.79 ± 0.06 (8) | 0.64 ± 0.11 (9) | 0.66 ± 0.19 (9) | 0.66 ± 0.14 (10) | 0.74 ± 0.16 (9) |
| Buschke (delayed: total correct-free) | 0.89 ± 0.09 (7) | 0.66 ± 0.30 (9) | 0.73 ± 0.25 (9) | 0.71 ± 0.18 (10) | 0.76 ± 0.23 (9) |
| Verbal fluency tests | |||||
| Verbal fluency (I) | 8.6 ± 3.5 (8) | 6.6 ± 4.0 (8) | 7.8 ± 3.1 (9) | 5.6 ± 3.8 (10) | 10.9 ± 5.1 (9) |
| Verbal fluency (K) | 5.9 ± 2.0 (8) | 4.9 ± 3.1 (8) | 5.8 ± 3.1 (9) | 5.3 ± 2.7 (10) | 6.8 ± 3.2 (9) |
| Verbal fluency (P) | 13 ± 2.7 (8) | 13 ± 6.2 (8) | 13 ± 6.4 (9) | 11.5 ± 5.1 (10) | 16 ± 4.6 (9) |
| Categorical fluency | 21 ± 5.5 (8) | 18 ± 6.7 (8) | 15 ± 5.7 (9) | 18 ± 4.9 (10) | 21 ± 6.4 (9) |
| Attention and executive function tests | |||||
| VSLT I (immediate) | 4.0 ± 1.6 (8) | 2.6 ± 1.1 (9) | 3.8 ± 1.8 (9) | 3.2 ± 1.7 (10) | 3.8 ± 2.6 (9) |
| VSLT II (delayed) | 4.5 ± 2.5 (8) | 4.3 ± 2.1 (9) | 5.2 ± 2.2 (9) | 4.3 ± 2.1 (10) | 4.3 ± 2.8 (9) |
| Letter–number sequencing | 0.45 ± 0.14 (8) | 0.39 ± 0.15 (8) | 0.47 ± 0.09 (9) | 0.44 ± 0.08 (10) | 0.43 ± 0.20 (9) |
| Stroop interference test | 59 ± 20 (8) | 64 ± 18 (9) | 55 ± 9.1 (10) | 53 ± 5.0 (10) | 57 ± 22 (9) |
| Trails B | 108 ± 63 (7) | 141 ± 86 (8) | 118 ± 42 (7) | 102 ± 48 (10) | 108 ± 87 (8) |
| Mazes | 102 ± 23 (6) | 184 ± 134 (8) | 177 ± 88 (9) | 131 ± 98 (10) | 144 ± 75 (9) |
Data represent mean ± SD or n (%)
Route learning score reflects baseline score out of 16 possible correct items
Complex figure score reflects baseline score out of 9 possible correct items
Paragraph recall score reflects baseline score out of 44 possible correct items
Buschke immediate and delay scores reflect baseline score out of 60 and 12 possible correct items, respectively
Letter–number sequencing score reflects baseline score out of 21 possible correct items
BMI body mass index, SHBG sex hormone-binding globulin, VSLT visual spatial learning test
Hormone levels
Baseline mean total and free testosterone concentrations were 13.1 ng/dl and 1.1 pg/ml, respectively, well below the range for healthy, menstruating women [17]. Serum nadir total and free testosterone levels, measured during week 24, increased from baseline in a dose-dependent fashion. Mean on-treatment nadir total testosterone concentrations were 15, 89, 98, 134, and 234 ng/dl, and mean free testosterone concentrations were 2.7, 14, 15, 24, and 44 pg/ml at the 0, 3, 6.25, 12.5, and 25 mg doses, respectively.
Cognitive function
The participants in different groups were similar at baseline in their performance on various tests of cognition (Table 1). There were no significant dose-dependent changes in the measures of spatial ability, verbal memory, verbal fluency or attention, and executive function from baseline to end of treatment after adjusting for baseline scores, age, and education (dose effect, all p values >0.05; Table 2). We also compared individual active doses to placebo using ANCOVA adjusting for these same covariates and found no significant differences (p value >0.05 for all comparisons; Supplementary Table 1). The changes in cognitive test scores from baseline in any of the domains tested were not significantly related to changes in total or free testosterone concentrations after adjusting for baseline scores, age, and education (all p values >0.05; Supplementary Table 2).
Table 2.
Change in cognitive function test scores by treatment group
| Dose of testosterone enanthate (mg/week)
| ||||||
|---|---|---|---|---|---|---|
| Cognitive test | Placebo | 3 mg | 6.25 mg | 12.5 mg | 25 mg | Dose effect p value |
| Visual spatial tests | ||||||
| Route learning test (immediate) | 0.03 ± 0.23 | 0.07 ± 0.19 | 0.06 ± 0.22 | −0.006 ± 0.16 | 0.10 ± 0.25 | 0.66 |
| Route learning test (delayed) | 0.08 ± 0.28 | −0.07 ± 0.25 | 0.15 ± 0.26 | −0.05 ± 0.21 | 0.03 ± 0.26 | 0.51 |
| Complex figure (immediate) | −0.04 ± 0.12 | 0.07 ± 0.16 | 0.11 ± 0.11 | 0.06 ± 0.10 | 0.06 ± 0.10 | 0.34 |
| Complex figure (delayed) | 0.04 ± 0.18 | 0.08 ± 0.14 | 0.11 ± 0.10 | 0.11 ± 0.12 | 0.19 ± 0.21 | 0.72 |
| Verbal memory tests | ||||||
| Paragraph (immediate) | 0.001 ± 0.100 | 0.03 ± 0.08 | 0.04 ± 0.06 | 0.07 ± 0.09 | 0.04 ± 0.17 | 0.99 |
| Paragraph (delayed) | 0.07 ± 0.10 | 0.08 ± 0.10 | 0.13 ± 0.08 | 0.03 ± 0.19 | 0.09 ± 0.13 | 0.30 |
| Buschke (immediate: total correct) | 0.08 ± 0.10 | 0.17 ± 0.10 | 0.02 ± 0.07 | 0.18 ± 0.15 | 0.06 ± 0.04 | 0.21 |
| Buschke (delayed: total correct) | 0.06 ± 0.09 | 0.20 ± 0.28 | 0.08 ± 0.12 | 0.17 ± 0.22 | 0.01 ± 0.11 | 0.87 |
| Verbal ability/language tests | ||||||
| Verbal fluency (I) | 1.4 ± 6.1 | 0.33 ± 2.25 | 1.2 ± 4.4 | 0.14 ± 3.0 | 0.00 ± 2.2 | 0.96 |
| Verbal fluency (K) | 2.1 ± 5.1 | −0.83 ± 2.32 | 0.20 ± 4.7 | 0.86 ± 3.5 | −1.4 ± 3.3 | 0.43 |
| Verbal fluency (P) | 2.1 ± 2.7 | −0.67 ± 1.37 | 0.80 ± 6.4 | −0.14 ± 4.3 | −1.3 ± 4.5 | 0.68 |
| Category fluency | 1.00 ± 8.4 | 2.5 ± 2.8 | 2.6 ± 1.9 | 1.3 ± 4.0 | −2.7 ± 4.9 | 0.78 |
| Attention and executive function tests | ||||||
| VSLT (immediate) | 1.2 ± 1.3 | 2.3 ± 1.4 | 0.24 ± 1.4 | 1.8 ± 1.9 | 0.63 ± 1.1 | 0.24 |
| VSLT (delayed) | 1.5 ± 2.4 | −0.14 ± 1.8 | 0.00 ± 0.71 | 1.3 ± 2.1 | 0.43 ± 0.79 | 0.40 |
| Letter–number sequencing | 0.06 ± 0.10 | −0.02 ± 0.09 | 0.01 ± 0.08 | −0.03 ± 0.09 | 0.007 ± 0.06 | 0.18 |
| Stroop interference test | −9.4 ± 11.1 | −7.9 ± 13.5 | −3.3 ± 8.9 | −6.9 ± 7.0 | −3.9 ± 9.3 | 0.92 |
| Trails B (s) | −4.0 ± 53.4 | −17 ± 41 | −28 ± 12 | −22 ± 19 | 14 ± 30 | 0.44 |
| Mazes (s) | 23 ± 63 | −41 ± 127 | 29 ± 60 | 2.0 ± 14.2 | −13 ± 85 | 0.27 |
Data represent mean ± SD of the change in cognitive test scores from baseline by dose group
The p value displayed represents the significance level of the overall dose effect after adjustment for baseline scores, age, and education
Route learning score reflects change from baseline score out of 16 possible correct items
Complex figure score reflects change from baseline score out of 9 possible correct items
Paragraph recall score reflects change from baseline score out of 44 possible correct items
Buschke immediate and delay scores reflect change from baseline score out of 60 and 12 possible correct items, respectively
Letter–number sequencing score reflects change from baseline score out of 21 possible correct items
VSLT visual spatial learning test
Discussion
In this trial of hysterectomized women with low testosterone levels, short-term testosterone administration over a wide range of doses was not associated with significant changes in cognitive function. Data from epidemiologic studies in specific patient populations have suggested that serum testosterone levels in women influence specific aspects of cognition. For example, women with PCOS perform better on spatial tasks and worse on verbal tasks compared to controls [10, 11]. Similarly, endogenous testosterone levels during the menstrual cycle are positively correlated with visuospatial ability and negatively with verbal fluency in healthy women [12, 20]. In female-to-male transsexuals, administration of supraphysiologic doses of testosterone worsens verbal fluency and improves spatial skills [20]. Contrary to these studies, our 24-week dose–response study did not show improvement or worsening of cognitive performance in a number of domains of cognitive function (spatial reasoning, verbal memory, verbal fluency, and executive function) over a wide range of testosterone doses and concentrations, including doses that achieved supraphysiologic serum testosterone concentrations.
The effects of testosterone administration on cognitive performance in postmenopausal women have not been extensively studied in the setting of clinical trials. In a study of surgically menopausal women, the addition of testosterone to estrogen replacement had a negative effect on immediate verbal memory compared with estrogen replacement alone [22]. These findings stand in contrast to those observed in women with hypopituitarism where no changes in cognitive function were observed during administration of transdermal testosterone for 12 months [23]. Although androgen effects on cognitive function are domain specific, previous trials of androgen replacement have evaluated only a limited number of cognitive domains. Furthermore, most trials have only used a single dose of testosterone, and therefore the dose-dependent effects of testosterone on cognition have not been previously demonstrated.
Our study has notable strengths and some limitations. The trial had many features of a good trial design: concealed randomization, placebo control, blinding, and oversight by an independent DSMB. Total and free testosterone levels were measured using LC–MS/MS and equilibrium dialysis, respectively; both widely considered the reference methods with the highest sensitivity and specificity. Unlike other studies, we characterized a comprehensive range of cognitive functions using well-validated neuropsychological tests with emphasis on domains reported to be affected by testosterone. However, measurement of cognitive function was not the primary outcome of the trial, and the trial was not designed to detect a difference in changes in cognitive measures. Our analysis was therefore limited by small sample size that may have had insufficient power to detect small effects. The 6-month duration of intervention may not have been long enough to demonstrate a significant change in cognitive function. Based on previous trials of hormone replacement and cognition [6], we would expect that the trial duration would be adequate to detect an effect of testosterone on cognition. As some trials have reported adverse effects of estrogen replacement on cognition, it is possible that positive effects of testosterone administration on cognition may have been attenuated with concurrent estrogen therapy. Finally, the women in our study were not recruited for impairments in cognition; hence, it is conceivable that testosterone replacement might be beneficial in women with baseline cognitive deficits. Although we excluded women with psychiatric disorders by self-report and review of their medical history, future trials should incorporate standardized assessments for mental health to ensure exclusion based on this potential confounding factor.
In conclusion, testosterone administration over a wide range of doses for 24 weeks in hysterectomized women with low testosterone levels was not associated with either beneficial or harmful effects on cognitive function. Long-term, adequately powered trials are needed to evaluate the cognitive effects of testosterone therapy in women. Based on the findings of our trial, short-term use of testosterone could be considered in select populations of women with low testosterone levels to improve sexual function and body composition without the concern of worsening cognitive function.
Supplementary Material
Acknowledgments
This study was supported by Grants 5U54HD041748-04 (to Charles Drew University of Medicine and Science) and 2008 TF D2274G (sub award to Boston University) from the National Institute of Child Health and Human Development and the Boston Claude D. Pepper Older Americans Independence Center Grant #5P30AG031679 from the National Institute of Aging. Watson Pharmaceuticals provided the transdermal estradiol patch for this trial. ENDO Pharmaceuticals provided testosterone injections for this trial.
Footnotes
Clinical Trials Registration Number: NCT00494208.
Electronic supplementary material The online version of this article (doi:10.1007/s40618-014-0213-3) contains supplementary material, which is available to authorized users.
Conflict of interest Dr. Basaria has received Grant support from Abbott Pharmaceuticals for investigator-initiated studies unrelated to this study and has previously consulted for Eli Lilly, Inc. Dr. Bhasin has received research Grant support from Abbott Pharmaceuticals and Eli Lilly, Inc. for investigator-initiated research unrelated to this study. Dr. Bhasin has served as a consultant to Regeneron, Merck, and Eli Lilly, Inc.
Data safety monitoring board Dr. Jan Shifren, Massachusetts General Hospital, Boston, Massachusetts (Chair); Dr. Raja Sayegh, Boston Medical Center; and Dr. Anita Nelson, Harbor-UCLA Medical Center.
Additional contributions We are grateful to Maithili Davda for her contribution to the statistical programming and data analysis for this manuscript. We thank the staff of the General Clinical Research Unit of Boston University’s Clinical and Translational Science Institute and the Clinical Research Center of Charles Drew University of Medicine and Science for their help with these studies and the study participants for their commitment and generosity.
Contributor Information
G. Huang, Email: ghuang7@partners.org, Section of Men’s Health: Aging and Metabolism, Harvard Medical School, Brigham and Women’s Hospital, BLI-5, 221 Longwood Avenue, Boston, MA 02115, USA.
W. Wharton, Department of Neurology, Emory University, WWHC 1841 Clifton Rd., NE, Atlanta, GA 30329, USA
T. G. Travison, Section of Men’s Health: Aging and Metabolism, Harvard Medical School, Brigham and Women’s Hospital, BLI-5, 221 Longwood Avenue, Boston, MA 02115, USA
M. H. Ho, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
C. Gleason, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Wisconsin Alzheimer’s Disease Research Center, Madison, WI 53792, USA.
S. Asthana, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Wisconsin Alzheimer’s Disease Research Center, Madison, WI 53792, USA.
S. Bhasin, Section of Men’s Health: Aging and Metabolism, Harvard Medical School, Brigham and Women’s Hospital, BLI-5, 221 Longwood Avenue, Boston, MA 02115, USA
S. Basaria, Section of Men’s Health: Aging and Metabolism, Harvard Medical School, Brigham and Women’s Hospital, BLI-5, 221 Longwood Avenue, Boston, MA 02115, USA
References
- 1.Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. New Engl J Med. 2000;343:682–688. doi: 10.1056/NEJM200009073431002. [DOI] [PubMed] [Google Scholar]
- 2.Dobs AS, Nguyen T, Pace C, Roberts CP. Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab. 2002;87:1509–1516. doi: 10.1210/jcem.87.4.8362. [DOI] [PubMed] [Google Scholar]
- 3.Fooladi E, Bell RJ, Jane F, Robinson PJ, Julkarni J, Davis SR. Testosterone improves anti-depressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial. J Sex Med. 2014;11:831–839. doi: 10.1111/jsm.12426. [DOI] [PubMed] [Google Scholar]
- 4.Maccoby EE, Jacklin CN. The psychology of sex differences. Stanford University Press; Stanford, California: 1974. [Google Scholar]
- 5.Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience. 2000;101:485–512. doi: 10.1016/s0306-4522(00)00410-3. [DOI] [PubMed] [Google Scholar]
- 6.Hogervorst E, Bandelow S. Sex steroids to maintain cognitive function in women after the menopause: a meta-analyses of treatment trials. Maturitas. 2010;66:56–71. doi: 10.1016/j.maturitas.2010.02.005. [DOI] [PubMed] [Google Scholar]
- 7.Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D, Investigators W Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2663–2672. doi: 10.1001/jama.289.20.2663. [DOI] [PubMed] [Google Scholar]
- 8.Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J, Women’s Health Initiative Memory S Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291:2959–2968. doi: 10.1001/jama.291.24.2959. [DOI] [PubMed] [Google Scholar]
- 9.Simpson E, Rubin G, Clyne C, Robertson K, O’Donnell L, Jones M, Davis S. The role of local estrogen biosynthesis in males and females. Trends Endocrinol Metab. 2000;11:184–188. doi: 10.1016/s1043-2760(00)00254-x. [DOI] [PubMed] [Google Scholar]
- 10.Schattmann L, Sherwin BB. Testosterone levels and cognitive functioning in women with polycystic ovary syndrome and in healthy young women. Horm Behav. 2007;51:587–596. doi: 10.1016/j.yhbeh.2007.02.007. [DOI] [PubMed] [Google Scholar]
- 11.Barry JA, Parekh HS, Hardiman PJ. Visual-spatial cognition in women with polycystic ovarian syndrome: the role of androgens. Hum Reprod. 2013;28:2832–2837. doi: 10.1093/humrep/det335. [DOI] [PubMed] [Google Scholar]
- 12.Hausmann M, Slabbekoorn D, Van Goozen SH, Cohen-Kettenis PT, Gunturkun O. Sex hormones affect spatial abilities during the menstrual cycle. Behav Neurosci. 2000;114:1245–1250. doi: 10.1037//0735-7044.114.6.1245. [DOI] [PubMed] [Google Scholar]
- 13.Ryan J, Stanczyk FZ, Dennerstein L, Mack WJ, Clark MS, Szoeke C, Kildea D, Henderson VW. Hormone levels and cognitive function in postmenopausal midlife women. Neurobiol Aging. 2012;33:1138–1147. doi: 10.1016/j.neurobiolaging.2012.04.011. [DOI] [PubMed] [Google Scholar]
- 14.Barrett-Connor E, Goodman-Gruen D. Cognitive function and endogenous sex hormones in older women. J Am Geriatr Soc. 1999;47:1289–1293. doi: 10.1111/j.1532-5415.1999.tb07427.x. [DOI] [PubMed] [Google Scholar]
- 15.Moffat SD, Hampson E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology. 1996;21:323–337. doi: 10.1016/0306-4530(95)00051-8. [DOI] [PubMed] [Google Scholar]
- 16.Davis SR, Jane F, Robinson PJ, Davison SL, Worsley R, Maruff P, Bell RJ. Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy. Clin Endocrinol (Oxf) 2014;81:621–628. doi: 10.1111/cen.12459. [DOI] [PubMed] [Google Scholar]
- 17.Huang G, Basaria S, Travison TG, Ho MH, Davda M, Mazer NA, Miciek R, Knapp PE, Zhang A, Collins L, Ursino M, Appleman E, Dzekov C, Stroh H, Ouellette M, Rundell T, Baby M, Bhatia NN, Khorram O, Friedman T, Storer TW, Bhasin S. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Menopause. 2013 doi: 10.1097/GME.0000000000000093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Huang G, Tang E, Aakil A, Anderson S, Jara H, Davda M, Stroh H, Travison TG, Bhasin S, Basaria S. Testosterone dose-response relationships with cardiovascular risk markers in androgen-deficient women: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2014:jc20134160. doi: 10.1210/jc.2013-4160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cohen J. Statistical power analysis for the behavioral sciences. 2nd. Routledge; Hillsdale: 1988. [Google Scholar]
- 20.Hampson E. Variations in sex-related cognitive abilities across the menstrual cycle. Brain Cogn. 1990;14:26–43. doi: 10.1016/0278-2626(90)90058-v. [DOI] [PubMed] [Google Scholar]
- 21.Slabbekoorn D, van Goozen SH, Megens J, Gooren LJ, Cohen-Kettenis PT. Activating effects of cross-sex hormones on cognitive functioning: a study of short-term and long-term hormone effects in transsexuals. Psychoneuroendocrinology. 1999;24:423–447. doi: 10.1016/s0306-4530(98)00091-2. [DOI] [PubMed] [Google Scholar]
- 22.Moller MC, Bartfai AB, Radestad AF. Effects of testosterone and estrogen replacement on memory function. Menopause. 2010;17:983–989. doi: 10.1097/gme.0b013e3181dc2e40. [DOI] [PubMed] [Google Scholar]
- 23.Miller KK, Biller BM, Beauregard C, Lipman JG, Jones J, Schoenfeld D, Sherman JC, Swearingen B, Loeffler J, Klibanski A. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2006;91:1683–1690. doi: 10.1210/jc.2005-2596. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.