Effects of the pharmacologic manipulation of testosterone on cognitive functioning in women with polycystic ovary syndrome: a randomized, placebo-controlled treatment study

In a previous study, we found that women with polycystic ovary syndrome (PCOS), an endocrine disorder characterized by chronic hyperandrogenism, performed more poorly than healthy, matched controls on a number of neuropsychological tests, in particular tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory. This randomized, placebo-controlled trial was undertaken to investigate whether pharmacologic manipulation of free testosterone (free T) levels in women with PCOS might affect their performance on cognitive tests. Nineteen women with PCOS completed a battery of neuropsychological tests before and after 3 months of treatment with either an anti-androgen (cyproterone acetate) plus estrogen or with a placebo. Hormone treatment of women with PCOS caused a significant reduction in their free T levels but did not affect performance on tests visuospatial ability, verbal memory, manual dexterity, or perceptual speed. Women treated with hormone therapy did, however, demonstrate an improvement in their performance on a test of verbal fluency compared to their pre-treatment scores. These findings suggest that changes in free T levels do not have a significant impact on cognitive performance in women with PCOS, although reductions in free T may be beneficial for verbal fluency.     

Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men

Relatively few studies have investigated the relationship between endogenous sex steroid levels and cognition in older people and the reported results have been inconsistent. A number of experimental hormone replacement studies have suggested that estrogen replacement in older women enhances cognition, especially verbal memory. In contrast, little research has been done focusing on men. In the current study the association between endogenous sex steroids (estradiol and testosterone) and cognition was investigated in 38 healthy older women (mean age 68 years) and 30 healthy older men (mean age 69 years). Five cognitive tests measuring verbal memory, spatial memory, verbal fluency, mental rotation, and susceptibility to interference were administered. Results revealed that in women higher estradiol levels as well as testosterone levels were associated with better verbal memory (paired associates and estradiol; r =.38, P < 0.05; paired associates and testosterone; r =.33, P < 0.05;). Moreover estradiol, but not testosterone was associated with less susceptibility to interference (Stroop color word test; r = -0.34, P < 0.05). In men the only significant association was a negative correlation between testosterone and verbal fluency (r = -0.38, P < 0.05). The associations observed in this small study support the notion that estradiol is protecting verbal memory and possibly also frontal lobe mediated functions in older women. In contrast to the positive findings in women endogenous sex steroids do not appear to be closely linked to better cognition in older men.     

Thyroid hormones and cognitive functioning in healthy, euthyroid women: a correlational study

Thyroid hormones (THs) play a critical role in differentiation, growth, and metabolism of animal and human organ systems, including the brain. Although associations between normal levels of THs and cognitive functions in healthy elderly individuals have been reported, the findings are inconsistent, possibly due to differences in study designs. Because thyroid disease occurs more frequently in women, the goal of the present study was to examine the relationship between levels of THs and performance on neuropsychological tests in 122 healthy, euthyroid women whose mean age was 51 years. Higher levels of free T3 were positively associated with longer completion times (slower performance) on Trail Making Test - Part A (p = 0.006) and Part B (p = 0.032) and on the Tower of London test (p = 0.002). Higher levels of thyroglobulin antibodies (TgAb) were positively correlated with more errors on the Trail Making Test Part B (p = 0.000), on the Word Fluency test (p = 0.023), and on the Design Fluency test (p = 0.045). No significant correlations between TH levels and scores on mood, verbal memory, or working memory measures were observed. The findings point to a possible link between THs and cognitive processes that are mediated primarily by frontal cortex, areas associated with executive function tasks, and suggest that elevations in levels of free T3 and TgAB within the normal range may negatively influence executive functions.     

Endogenous testosterone levels, mental rotation performance, and constituent abilities in middle-to-older aged men

Evidence from both human and animal studies suggests that gonadal steroids, such as testosterone, exert activational effects on adult spatial behavior. Endogenous testosterone levels decline gradually but variably as men age; it remains to be shown whether these decreases are associated with age-related declines in visuo-spatial performance or constituent abilities indicative of generalized age-related cognitive decline. Ninety-six healthy, community dwelling men aged between 38 and 69 years completed the Vandenberg and Kuse Mental Rotation Test (MRT) together with a battery of tests including processing speed, executive function, perceptual discrimination, working memory, and reaction time measures. Significant main effects of tertiles of calculated free testosterone levels (cEFT) were found on composite measures of processing speed, executive function, and perceptual discrimination ability in a subset of men aged over 50 years in age and crystallized intelligence controlled analyses; higher cEFT levels were associated with poorer performance. Hierarchical multiple regression and path analyses on the whole data set showed that cEFT levels negatively moderated processing speed performance, which in turn predicted both working memory and MRT performance with aging. Together these data suggest that age-related declines in endogenous testosterone levels in healthy middle-to-older aged men are not associated with generalized age-related cognitive decline.     

Cognitive outcome in adult women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency

BACKGROUND: Some research suggests that girls with congenital adrenal hyperplasia (CAH), who are exposed to higher than normal levels of prenatal androgens, perform better on spatial tasks, worse on verbal tasks and have a greater incidence of left-handedness than unaffected controls, all of which suggests the development of a more male-typical cognitive pattern. However, research in all three areas has produced inconsistent findings. OBJECTIVES: To determine if prenatal androgen exposure has an organizing effect on female cognitive development and to what extent. METHODS: 24 women, 21-71 years, with either the salt-losing (SL) or simple virilizing (SV) forms of CAH due to 21-hydroxylase deficiency, and 18 controls, 21-73 years, who were unaffected female relatives or women with polycystic ovary syndrome, were assessed with IQ, handedness, executive function, verbal learning and memory, non-verbal learning and memory, perceptual speed, visuospatial processing and visuomotor ability measures. The battery included tests known to elicit sex differences and control measures. RESULTS: The findings did not support the hypothesis that women with CAH develop a more male-typical cognitive pattern. CONCLUSION: This study differs from others in the older age of its participants, grouping by SL/SV diagnosis and assessment of medical treatment and compliance as determined through hormone assays. Our findings provide additional support for the conclusion that, in adult women with CAH, previous prenatal androgen exposure does not enhance spatial abilities, impair verbal abilities nor alter hand preferences in a long-lasting way.     

Sex steroid hormones and cognitive functioning in healthy, older men

The precise impact of age-related changes in hormone levels on cognition in men is still unclear due to differing study designs and contradictory findings. This study was undertaken to examine the relationship between endogenous sex hormone levels and cognitive functioning in healthy older men using a comprehensive battery of neuropsychological tests and measurement of serum sex hormone levels. Verbal learning and memory, visual-motor processing, spatial abilities, working memory and attention, and levels of testosterone and estradiol were evaluated in 54 healthy older men. Regression analyses revealed significant curvilinear associations between working memory function and both free and bioavailable testosterone levels, suggesting that an optimal hormone level may exist for maximal performance on tasks of executive/frontal lobe functioning. However, no other relationships were evident between either estradiol or testosterone levels and any of the other cognitive functions evaluated. Hormone assays performed at the end of the study revealed that a considerable portion of the healthy elderly men in our sample met criteria for hypogonadism and suggests that their low hormone levels may have mitigated against discovering other significant hormone-cognition relationships.     

Salivary testosterone does not predict mental rotation performance in men or women

Multiple studies report relationships between circulating androgens and performance on sexually differentiated spatial cognitive tasks in human adults, yet other studies find no such relationships. Relatively small sample sizes are a likely source of some of these discrepancies. The present study thus tests for activational effects of testosterone (T) using a within-participants design by examining relationships between diurnal fluctuations in salivary T and performance on a male-biased spatial cognitive task (Mental Rotation Task) in the largest sample yet collected: 160 women and 177 men. T concentrations were unrelated to within-sex variation in mental rotation performance in both sexes. Further, between-session learning-related changes in performance were unrelated to T levels, and circadian changes in T were unrelated to changes in spatial performance in either sex. These results suggest that circulating T does not contribute substantially to sex differences in spatial ability in young men and women. By elimination, the contribution of androgens to sex differences in human performance on these tasks may be limited to earlier, organizational periods.     

Testosterone, cognition, and social status

What leads some people to perform better than others on certain cognitive tasks? One explanation involves individual differences in testosterone. Testosterone is associated with higher performance on spatial tests, and lower performance on verbal tests. However, a large literature suggests that testosterone only predicts behavior when status is in jeopardy. In the present study, we manipulated status before administering a spatial and verbal test. In a high-status position, high-testosterone individuals performed well on both tests, and blood pressure dropped. In a low-status position, high-testosterone individuals performed relatively poorly on both tests, and blood pressure did not change. These data suggest that differences in cognitive performance stem from an interaction between testosterone and the social situation.     

Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance

BACKGROUND/AIMS: Insulin resistance is associated with serum C-reactive protein (CRP) levels. We aimed to evaluate the effect of bicalutamide on insulin resistance and serum CRP levels in non-obese polycystic ovarian syndrome (PCOS) patients. METHODS: 40 non-obese patients (BMI < or =25 kg/m2) with PCOS and, 40 age- and BMI-matched healthy women were studied. Patients received bicalutamide orally at the dose of 25 mg/day. Serum CRP levels were measured with immunometric assay. Homeostasis model assessment (HOMA-IR) index was used for insulin resistance. RESULTS: Mean Ferriman-Gallwey score (FGS) (p = 0.001), insulin (p = 0.001), serum glucose (p = 0.001), prolactin (p < 0.003), total (p < 0.04) and free testosterone (p = 0.001) and free androgen index (FAI) levels (p = 0.001) of PCOS subjects were higher than in the control group. Mean HOMA-IR of PCOS patients was higher than in control subjects (2.43 +/- 1.2 and 0.94 +/- 0.37, p = 0.001). CRP levels in subjects with PCOS was also higher than in control subjects (4.27 +/- 1.33 and 0.98 +/- 0.19, p = 0.001). After bicalutamide treatment, FGS, free and total testosterone and FAI decreased (p = 0.001). HOMA-IR, prolactin and CRP levels did not show any statistical difference with bicalutamide treatment. CONCLUSIONS: PCOS patients had insulin resistance and a high CRP level. Bicalutamide treatment did not influence insulin resistance and CRP level in PCOS, and this ineffectiveness of bicalutamide on CRP levels may be the result of insulin resistance and/or high prolactin levels at this time.     

The effects of exogenous testosterone on spatial memory in rats

Testosterone (T) is known to affect spatial abilities in men and women. Studies focusing on this relationship showed that both endogenous variability of T and administration of exogenous T, altered mental rotation and spatial visualization. Organizational and activational effects of T can be separately identified. The aim of our study was to evaluate the activational effects of exogenous T on spatial memory in male and female rats. T was administered 3 times a week over a two week period in either 1 mg/kg for low testosterone group or 10 mg/kg for high testosterone group. The Morris water maze was performed to assess the rat’s working and reference spatial memory. T and estradiol levels were measured in plasma. Increase in plasma T levels was confirmed in the experimental groups in comparison to the control groups (receiving sterile oil, 3 times a week over a two week period). Low dose T impaired working, but improved reference memory in female rats. In male rats the negative effects of T (both doses) on reference memory were shown. This experiment showed that the activational effects of exogenous testosterone on spatial memory of rats were gender and dose-dependent.     

Estradiol treatment and its interaction with the cholinergic system: effects on cognitive function in healthy young women

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.     

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.     

Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women

The cholesterol side chain cleavage enzyme (CYP11A1) gene plays an important part in the synthesis of sex hormones and has been reported to be involved in the pathogenesis of polycystic ovary syndrome. A case-control study including 314 PCOS patients and 314 controls was conducted to assess the association of the SNPs rs4077582 and rs11632698 in CYP11A1 with PCOS using the polymerase chain reaction-restriction fragment length polymorphism method. Thereafter, 100 DNA samples were re-genotyped by direct sequencing for confirmation. The genotypic distribution of rs4077582 in women with PCOS differed from that in controls (P = 0.002). No such distributional difference was found in rs11632698 (P = 0.912). Data from our previous study of these two SNPs in another population including 290 PCOS patients and 344 controls was combined with the current data. Combined analysis (a total of 1262 participants, including 604 PCOS patients and 658 control women) showed a much more significant difference in the genotypic distribution of rs4077582 between PCOS and controls (P < 0.001). The T allele was more prevalent in PCOS patients (Odds ratio = 1.314; 95 % CI 1.122-1.540). The testosterone levels among the three genotypes for rs4077582 were different in the control group, as were the LH levels and the LH/FSH ratio. Therefore, SNP rs4077582 in CYP11A1 is strongly associated with susceptibility to PCOS and may alter the testosterone levels by the regulation of LH in different genotypes. No association was observed in rs11632698.     

Plasma level of calcitonin gene-related peptide in patients with polycystic ovary syndrome and its relationship to hormonal and metabolic parameters

The aim of the study was to evaluate the plasma level of calcitonin gene-related peptide (CGRP) in patients with polycystic ovary syndrome (PCOS) and its relationship to hormonal and metabolic parameters. We also observed the effect of CGRP on testosterone (T) and estradiol (E(2)) release in cultured human granulosa cells. PCOS subjects (n=215) and matched healthy control women (n=103) at age of 22-38 years were enrolled in this study. We analyzed plasma CGRP concentrations, relationship of plasma CGRP with insulin resistance (IR), body mass index (BMI), luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio and T. The T and E(2) release levels of cultured human granulosa cells treated by CGRP were also measured. The results showed that plasma CGRP concentrations were significantly higher in women with PCOS than those of control subjects. In women with PCOS, there was a strong positive correlation between the plasma CGRP level with HOMA-IR, AUC-insulin, AUC-glucose, the ratio of LH/FSH and plasma T concentration. Human granulosa cells expressed CGRP receptor. Exogenous CGRP caused an elevation of T and E(2) released from the human granulosa cells. These findings suggest that CGRP may participate in the pathophysiological process of PCOS.     

Susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21, and 9q33.3 in a cohort of Caucasian women

In a recent genome-wide association study investigating Han Chinese PCOS women 3 loci that are strongly associated with PCOS were identified on chromosome 2p16.3 (rs13405728), 2p21 (rs13429458), and 9q33.3 (rs2479106). The aim of the study was to investigate the impact of rs13405728, rs13429458, and rs2479106 variants on PCOS susceptibility in a Caucasian cohort of PCOS and control women. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed in 545 PCOS and 317 control women. The rs13405728, rs13429458, and rs2479106 polymorphisms were genotyped. There was no significant difference in genotype frequencies of rs13405728 and rs13429458 variants between PCOS and controls. There was a trend towards an association of the rs2479106 variant with PCOS susceptibility (p=0.053). PCOS women with the rs2479106 GG genotype had significantly higher WHR than PCOS women carrying the AG and AA genotype (p=0.034 and p=0.020, respectively). Moreover, QChol/HDL and LDL levels were significantly higher in PCOS women carrying the rs2479106 GG genotype when compared to those carrying the AA genotype (p=0.024 and p=0.035, respectively). PCOS women carrying the G allele of rs13405728 had significantly higher AUCgluc, glucose-30 min, and AUCins levels than those carrying the AA genotype (p=0.039, p=0.047, and p=0.044, respectively). In PCOS women, rs13405728 genotypes are associated with glucose and insulin metabolism. Moreover, rs2479106 genotypes were associated with increased WHR levels and an adverse serum lipid profile. Further, we observed a trend towards decreased PCOS susceptibility within carriers of the rs2479106 G-allele. Further studies in large Caucasian PCOS cohorts are warranted to confirm our findings.     

Circadian variations of serum sex hormone binding globulin binding capacity in normal adult men and women

Diurnal variations of serum sex hormone binding globulin (SHBG), testosterone (T) and estradiol (E2) in five normal adult men and five normal adult women were investigated. SHBG binding capacity was measured by both polyacrylamide gel electrophoresis and dextran-coated charcoal technique (DCC); T and E2 were assayed by RIA and free T and free E2 were determined by means of equilibrium dialysis. In male subjects the variations of SHBG binding capacity was associated with the changes of total T, free T and T/SHBG index, which had the highest concentrations in the morning and the lowest levels in the evening during the 24 h test period, but percentage free T remained unchanged. Serum protein concentrations did not change significantly during 24 h. No significant diurnal changes of SHBG binding capacity, total E2, free E2, percentage free E2 and percentage free T were found in female subjects in the mid-luteal phase of the menstrual cycle, although significant fluctuations of total T, free T and T/SHBG index were observed throughout the day. The results suggested that SHBG may play a buffer role in the presence of fluctuations of testosterone production during 24 h period, allowing stabilization of a bioactive fraction of the hormone both in normal adult male and female. However, the concentrations of T in normal adult women may be too low to drive any change of SHBG levels while there were no significant variations of E2 throughout a day in the mid-luteal phase of the menstrual cycle.     

Association Study between Polycystic Ovarian Syndrome and the Susceptibility Genes Polymorphisms in Hui Chinese Women

IntroductionPolycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders. Evidence of familial aggregation analysis and different clinical traits among different regions and ethnicities indicated that the pathogenesis of PCOS is associated with multiple genetic and environmental factors. Our previous research had identified three susceptibility loci (rs2479106, DENND1A; rs13405728, LHCGR; rs13429458, THADA) for PCOS in Han Chinese women. The overall aim of this study was to investigate the relationship between three susceptibility gene polymorphisms and PCOS in Hui ethnic women.Methods151 patients with PCOS (case group) and 99 healthy women (control group) were recruited from the Reproductive Medicine Center of the General Hospital of Ningxia Medical University. Clinical data and serum hormone characteristics of case and control groups were collected and analyzed. The three susceptibility single-nucleotide polymorphisms have been replicated in both case and control groups. Gene polymorphisms were detected by direct sequencing after polymerase chain reaction.ResultsThe Body Mass Index, LH, LH/FSH ratio and total testosterone were significantly elevated in PCOS patients compared to control group (P<0.05). The frequencies of genotype and allele in rs13405728 were significantly different between the PCOS and the control groups (P<0.05). Of the SNP rs13405728, the PCOS cases with TT genotype stayed at a higher level of total testosterone, TG and LDL than those with the CC and CT genotypes. In contrary, there was no statistical difference between the two groups for SNP rs13429458 and rs2479106 (P>0.05).ConclusionThe present study suggested that the SNP rs13405728 in the LHCGR gene was associated with PCOS in Hui ethnic women, and its TT genotype characterized with higher level of TT, TG and LDL.     

Fasting insulin pulsatile secretion in lean women with polycystic ovary syndrome

The aim of our study was to evaluate rapid insulin pulses and insulin secretion regularity in fasting state in lean women with polycystic ovary syndrome (PCOS) in comparison to lean healthy women. PCOS (n=8) and controls (n=7) underwent every minute blood sampling for 60 min. Insulin pulsatility was assessed by deconvolution and insulin secretion regularity by approximate entropy methodology. PCOS had higher testosterone (p<0.02), prolactin (p<0.05) and lower sex hormone binding globulin (SHBG) (p<0.0006) levels than controls. Approximate entropy, insulin pulse frequency, mass, amplitude and interpulse interval did not differ between PCOS and controls. PCOS had broader insulin peaks determined by a common half-duration (p<0.07). Burst mass correlated positively with testosterone (p<0.05) and negatively with SHBG (p 0.0004) and common half-duration correlated positively with prolactin (p<0.008) and cortisol levels (p<0.03). Approximate entropy positively correlated with BMI (p<0.04) and prolactin (p<0.03). Lean PCOS patients tended to have broader insulin peaks in comparison to healthy controls. Prolactin, androgens and cortisol might participate in alteration of insulin secretion in PCOS-affected women. Body weight and prolactin levels could influence insulin secretion regularity.     

Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels

The objective of the study was the comparison of anti-Müllerian hormone (AMH) levels among obese or overweight and normal-weight women with the four different polycystic ovary syndrome (PCOS) phenotypes and healthy control subjects. AMH levels were evaluated in four age- and body mass index (BMI)-matched groups of 25 normal-weight and 25 obese or overweight women each, belonging to the four main subsets of the syndrome resulting from combinations of the three diagnostic criteria [group 1: oligo- and/or anovulation (ANOV), hyperandrogenemia (HA), and polycystic ovaries (PCO) on ultrasonographic evaluation; group 2: ANOV and HA; group 3: HA and PCO, group 4: ANOV and PCO], and in 50 (25 obese or overweight and 25 normal weight) age- and BMI-matched healthy control subjects. Age, BMI, waist circumference, FSH, LH, prolactin, testosterone, Delta(4)-androstenedione, dehydroepiandrosterone-sulfate, 17alpha-OH-progesterone, fasting insulin, glucose, AMH, free androgen index, and homeostasis model assessment for insulin resistance index were analyzed. AMH levels were significantly higher in PCOS groups 1 and 2 compared with groups 3 and 4 and the control group and higher in PCOS groups 3 and 4 compared with the control group. AMH levels were significantly increased in normal-weight compared with obese and overweight women. AMH concentrations were independently predicted, in order of significance, by LH and testosterone levels, BMI (negatively), and the total number of follicles 2-9 mm in diameter. The differences in circulating AMH levels between the main phenotypic groups of PCOS women appear to reflect the severity of the syndrome, but are negatively affected by obesity. Increased LH levels might be the most significant independent link between PCOS-associated disorders of ovulation and the observed increase in circulating AMH concentration.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.