Hum Reprod Update. 2006 Nov 29; [Epub ahead of print]

Genazzani AR, Pluchino N, Luisi S, Luisi M.

Starting from fetal life, estrogens are crucial in determining central gender dimorphism, and an estrogen-induced synaptic plasticity is well evident during puberty and seasonal changes as well as during the ovarian cycle. Estrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, estrogen's neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults. Clinical evidences show that, during the climacteric period, estrogen withdrawal in the limbic system gives rise to modifications in mood, behaviour and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. Many biological mechanisms support the hypothesis that estrogens might protect against Alzheimer's disease (AD) by influencing neurotransmis-sion, increasing cerebral blood flow, modulating growth proteins associated with axonal elongation and blunting the neurotoxic effects of beta-amyloid. On the contrary, clinical studies of estrogen replacement therapy (ERT) and cognitive function have reported controversial results, indicating a lack of efficacy of estrogens on cognition in post-menopausal women aged >/=65 years. These findings suggest the presence of a critical period for HRT-related neuroprotection and underlie the potential importance of early initiation of therapy for cognitive benefit. In this review, we shall first describe the multiple effects of steroids in the nervous system, which may be significant in the ageing process. A critical update of HRT use in women and a discussion of possible prospectives for steroid use are subsequently proposed.

Neurobiol Aging. 2006 Oct 6; [Epub ahead of print]

Ha DM, Xu J, Janowsky JS.

Despite numerous studies showing neurotrophic and neuroprotective effects of estrogen in animal models, the long-term effects of estrogen use on brain morphology in older women are not known. Thus, we compared ventricular, cerebrospinal fluid, white matter, and grey matter volumes estimated from magnetic resonance images of postmenopausal women with more than 20 years exposure to unopposed estrogen, women who were not on estrogen, and young healthy women. Estrogen users had significantly smaller ventricles and greater white matter volumes than non-users, but hormone exposure did not affect grey matter volumes. Young healthy women had significantly smaller ventricles, less cerebrospinal fluid and more grey matter than both groups of older women. However, they had comparable white matter volumes to older women on estrogen. These findings suggest that long-term estrogen protects against white matter loss in aging. This adds to findings from other studies suggesting estrogen is neuroprotective of the hippocampus and other regions in older women.

Neurobiol Aging. 2006 Oct 6; [Epub ahead of print

Lord C, Buss C, Lupien SJ, Pruessner JC.

Considerable evidence suggests that estrogen can have neuroprotective effects. However, recent results raised important questions regarding the conditions under which hormone therapy (HT) following menopause can be beneficial. It has been suggested that variables such as time of initiation and duration of HT use are of critical importance for beneficial cognitive effects to be observed. The aim of the present study was to investigate the potential neuroprotective effects of estrogens in aging on brain regions with high levels of estrogen receptors, namely the hippocampus (HC) and the amygdala (AG). In order to better characterize the punctual and long-term effects of estrogens, we tested postmenopausal women currently using estrogen therapy alone (ET), past HT users, never users, and men. Age at menses, age at menopause, HT duration and age were included as covariates in the analysis. Results demonstrate that women using ET had larger left and right HC volumes compared to men, and larger right HC volumes compared to past users and never users. Importantly, we found a significant negative relationship between ET duration and HC volume in this group. The observed effects were region-specific since no significant differences could be observed for the AG. In summary, these findings support a treatment duration dependent neuroprotective role of estrogen on HC volume in aging.

Neurologist. 2006 May;12(3):149-59.

Henderson VW.

BACKGROUND:: Menopause is a normal milestone experienced annually by 2 million American women each year, and many women are concerned about the relation between menopause and health. Associated hormonal changes have the potential to influence neurologic disease, as do hormonal therapies prescribed for menopausal symptoms or other conditions. The objective of this article is to increase neurologists' awareness of the relation between menopause and neurologic illness. REVIEW SUMMARY:: This was a focused review of 4 common neurologic disorders potentially influenced by menopause or by estrogen-containing hormone therapy: stroke, epilepsy, Parkinson disease, and Alzheimer disease. Hormonal effects are germane to each illness, although clinical implications are clearer for stroke and Alzheimer disease than for epilepsy and Parkinson disease. For women with epilepsy, few clinical data directly address the role of menopause or estrogen-containing hormone therapy on seizure frequency. Relevant clinical research findings on Parkinson disease are inconsistent and provide an inadequate basis for practice guidelines. There is clinical trial evidence that hormone therapy does not reduce stroke incidence and may increase risk of ischemic stroke; hormone therapy cannot be recommended for stroke prevention. The natural menopausal transition is not characterized by objective memory loss. There is clinical trial evidence that hormone therapy should not be used for the postmenopausal woman age 65 years or older for the preservation of cognitive skills, prevention of dementia, or treatment of dementia due to Alzheimer disease. Long-term cognitive consequences of short-term hormone therapy used by younger women for menopausal symptoms remains an important area of uncertainty. CONCLUSIONS:: Increased awareness of hormonal influences on neurologic illness is important for the practicing neurologist.

Climacteric. 2006 Jun;9(3):181-94

No differences in performance on test of working memory and executive functioning between healthy elderly postmenopausal women using or not using hormone therapy.

Grigorova M, Sherwin BB.

Department of Psychology, McGill University, Montreal, Canada.

BACKGROUND: On average, ovarian function ceases at the age of 52 years so that estrogen (E) levels are chronically low following the menopause. Numerous studies have found that hormone therapy (HT) helps to protect verbal memory, a hippocampal function. Estrogen receptors are also found in the prefrontal cortex (PFC), suggesting that estrogen may modulate executive and working memory functions, both mediated by the PFC. The possible role of progesterone (P) on executive functions and working memory is unknown. OBJECTIVE: To examine the relationship between neuropsychological performance, age of initiation of HT, and duration of HT use. METHOD: In this cross-sectional study, the neuropsychological performance of 37 postmenopausal women (mean age, 65 years) who used either estrogen-only or sequential E + P (E-alone group)(n = 22) or E + P continuously (n = 15) was compared to that of 28 healthy postmenopausal women matched for age and education who had never used HT. It was hypothesized that the E-only users would perform better then the E + P and the never-users on neuropsychological tests of verbal memory, executive function and working memory. RESULTS: Results showed only minor between-group differences on working memory scores such that the E + P users were slowest to generate a response on the N-Back test of working memory. No group differences on tests of executive functions were found. CONCLUSION: There was no relationship between neuropsychological performance, age of initiation of HT, or duration of HT use.

Menopause. 2006 May 25; [Epub ahead of print]

Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women.

Joffe H, Hall JE, Gruber S, Sarmiento IA, Cohen LS, Yurgelun-Todd D, Martin KA.

Center for Behavioral Endocrinology, McLean Hospital, Harvard Medical School, Boston, MA

OBJECTIVE:: Estrogen therapy (ET) seems to differentially effect cognitive processes in younger versus older postmenopausal women, suggesting a window of opportunity when ET is most beneficial. Cognitive improvement in younger postmenopausal women has been attributed to ET's influence on hot flushes and sleep, but empiric examination of the mediating role of menopause symptoms versus direct effects of ET on the brain is limited. The aim of this study was to determine which cognitive domains are influenced by ET and whether hot flushes and sleep play mediating roles in these effects. DESIGN:: In a double-blind trial, 52 women were randomly assigned to estradiol 0.05 mg/day (n = 26) or placebo transdermal patches (n = 26) for 12 weeks. Women completed tests of memory, learning, and executive functioning, and hot flush and sleep assessments at baseline and study end. A subset of women (five ET treated, six placebo treated) also underwent blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. RESULTS:: Nondepressed perimenopausal and postmenopausal women were studied. The majority had hot flushes and sleep impairment. Compared with placebo, ET selectively reduced errors of perseveration during verbal recall (P = 0.03), a frontal system-mediated function, but did not influence other cognitive processes. Women with baseline hot flushes had greater cognitive benefit with ET (P < 0.05). Cognitive benefit was not associated with sleep problems or its improvement. Measures of fMRI BOLD activation during tests of verbal and spatial working memory showed significant increases in frontal system activity with ET (P < 0.001). CONCLUSIONS:: Estrogen therapy selectively improves executive functioning as demonstrated by reduced perseverative errors and prefrontal cortex activation during verbal recall tasks. Cognitive improvement with ET is associated with hot flushes, but not with sleep, suggesting that ET has a direct central nervous system effect, rather than an indirect effect mediated through improvement of sleep.

Menopause. 2006 May 25; [Epub ahead of print]

Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women.

Archer JS, Love-Geffen TE, Herbst-Damm KL, Swinney DA, Chang R J.

From the 1Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis, MN, USA

OBJECTIVE:: To determine the effect of estradiol and testosterone on brain-activation patterns in surgically postmenopausal women viewing erotic video clips using functional magnetic resonance imaging. DESIGN:: Six women, who had undergone a bilateral oophorectomy and hysterectomy for benign disease, viewed erotic and neutral videos during functional magnetic resonance imaging while not on hormone therapy, while on estradiol therapy, and while on estradiol and testosterone therapy. Five similarly aged premenopausal women viewed the same videos. Areas of brain activation between the functional magnetic resonance imaging scans of both groups of women were compared to determine whether agonadal serum levels of sex hormones and administration of estradiol and testosterone impacted brain patterns of sexual arousal. RESULTS:: When compared with premenopausal women, untreated postmenopausal women had significantly decreased areas of brain activation during both erotic and neutral stimulations. Administration of estradiol increased global brain-activation patterns during both visual stimulations, with erotic video viewing causing a limited increase in limbic system activation. Combined estradiol and testosterone therapy was associated with a greater activation of the central nervous system, with more limbic system activated during the erotic video. Brain-activation patterns of the postmenopausal women were similar to the premenopausal group only during the estradiol and testosterone treatment phase. CONCLUSIONS:: Agonadal serum hormone levels result in globally decreased brain-activation patterns in postmenopausal women while viewing neutral and erotic videos. Administration of both estradiol and testosterone increase global brain activation, and both sex steroids are independently associated with enhanced limbic system response during erotic visual stimulation.

Menopause. 2006 May 25; [Epub ahead of print]

Estradiol gel: review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women.

Naunton M, Al Hadithy AF, Brouwers JR, Archer DF.

Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, The Netherlands

OBJECTIVE:: To review the pharmacology, pharmacokinetics, safety, and efficacy of a gel containing estradiol that is applied to the skin. DESIGN:: MEDLINE and EMBASE searches were conducted from 1966 to March 2005. Additional references were identified from bibliographies from selected studies in addition to approved product information. RESULTS:: Estradiol gel is indicated for the relief of moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy. Women who are intolerant of the oral route, have had previous hypersensitivity skin reactions, or have had difficulties with adhesive patches are ideal candidates for estradiol gel. CONCLUSIONS:: Estradiol gel can effectively reduce menopause symptoms with minimal side effects. Long-term safety data of estradiol gel are required.

ORGYN.Com

Treatment-induced menopause linked to cognitive decline

Source: British Journal of Cancer 2006; 94: 828-34

Comparing the neuropsychological performance of women with early-stage breast cancer treated with chemotherapy and controls. Few women undergoing adjuvant therapy for early-stage breast cancer show a decline in cognitive performance, although those who experience a treatment-induced menopause are more at risk, researchers report. V Jenkins (University of Sussex, Brighton, UK) and co-authors monitored the neuropsychologic performance of women with early-stage breast cancer who received chemotherapy (n=85), and radiotherapy and/or endocrine therapy (n=43), along with 49 healthy women.The participants completed cognitive tests at baseline and after the final chemotherapy session or at 6-month follow-up. Overall, just 20 percent of chemotherapy-treated, 26 percent of nonchemotherapy-treated, and 18 percent of controls showed a reliable decline in their ability to perform multiple tasks at the second test. However, women who experienced a treatment-induced menopause during the study period were 2.6-times more likely to show a decline in performance at this point than the other individuals. Further research on this population would help clarify "whether it is a reduction in estrogen producing severe endocrine symptoms that interferes with attending to stimuli and therefore constrains memory processing, or chemotherapy treatment per se," Jenkins et al conclude.

Menopause. 2006 Jan-Feb;13(1):28-36

Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study.

MacLennan AH, Henderson VW, Paine BJ, Mathias J, Ramsay EN, Ryan P, Stocks NP, Taylor AW.

Department of Obstetrics and Gynaecology, Stanford University, CA, USA.

OBJECTIVE: The aim of this pilot study was to assess any trends related to the timing of initiation, and duration, of hormone therapy (HT) use on cognitive function to facilitate the design and power calculations for a future large cohort study entitled Research into Memory, Brain function and Estrogen Replacement (REMEMBER). DESIGN: A total of 428 women aged older than 60 years were recruited from a computer-generated random selection of Adelaide households. Demographic and lifestyle characteristics, and HT use history were recorded and confirmed. The Center for Epidemiological Studies-Depression score was used to assess mood. Cognitive tests were administered measuring global cognition (Mini-Mental State Examination), attention and concentration (Trail Making Test Parts A and B), verbal learning and memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list immediate and delayed recall), and verbal expression (letter fluency [FAS], category fluency [Animals], and the Boston Naming Test [short form]). Analyses were adjusted for age, education, mood, body mass index, smoking, alcohol intake, and history of cerebrovascular disease. HT use was defined as the use of systemic HT for at least 1 year. Early initiation of HT use was defined as commencement of HT before age 56 years for women with a uterus and ovaries, or within 5 years of a hysterectomy and bilateral oophorectomy. Late initiation of HT use was defined as HT commencing after these times. RESULTS: Early initiators of HT performed better than late initiators on the Mini-Mental State Examination (P = 0.04) and were faster than never users on the Trail Making Test Part A (P = 0.02). Women aged 70-79 years who initiated HT early performed better on the FAS test than never users (P = 0.0008). Late initiators performed worse than never users on the Mini-Mental State Examination (P = 0.09), and on the FAS test in the 60-69 year (P = 0.06) and 80 years and older (P = 0.095) age groups. However, late initiators performed better than never users on the FAS test in the 70-79 year age group (P = 0.015). HT users of less than 11 years (P = 0.09), HT users of more than 11 years (P = 0.04), and estrogen-only users (P = 0.024) performed faster than never users on the Trail Making Test Part A. Combined estrogen plus progestin users performed better than never users on the Boston Naming Test short form (P = 0.07). CONCLUSIONS: For some cognitive domains, early initiation of HT from around menopause may be beneficial, and initiation of HT in late menopause may be detrimental. The timing of the initiation of HT seems critical. To fully test these hypotheses and to further examine these trends by route and type of HT regimen in this population, a study size of 2,500 women would be required.

Menopause. 2006 Jan-Feb;13(1):19-27

Cognitive function across the life course and the menopausal transition in a British birth cohort.

Kok HS, Kuh D, Cooper R, van der Schouw YT, Grobbee DE, Wadsworth ME, Richards M.

MRC National Survey of Health and Development, Department of Epidemiology and Public Health, England.

OBJECTIVE: Despite biological plausibility, relationships between menopause and cognitive function are inconsistent. We investigated whether menopause status and menopause age were associated with general cognitive ability, verbal memory, and visual search speed and concentration in a large cohort of women while considering vasomotor and psychological symptoms, previous childhood and adult measures of cognitive function, lifetime socioeconomic circumstances, educational attainment, lifestyle factors, and chronic diseases. DESIGN: A nationally representative British cohort of 1261 women born in March 1946 and all aged 53 years at cognitive testing, with prospective information on previous cognitive function, menopausal characteristics, and potential confounders. RESULTS: There was only weak evidence of the effect of natural menopause on cognitive function and no evidence of any effects of hormone therapy use or hysterectomy status. There was a trend across the phases of the natural menopausal transition (pre-, peri-, and postmenopause) for the National Adult Reading Test (P = 0.005) and search speed and concentration (P = 0.042), with postmenopausal women having the lowest cognitive function, but there was no trend in verbal memory. Variation in vasomotor and psychological symptoms did not explain these trends. In postmenopausal women, there was a positive trend across menopause age for verbal memory (P = 0.004) and a weak positive trend for the National Adult Reading Test (P = 0.052), with women who reached menopause later having higher cognitive function. Previous cognitive function generally explained the associations, which were further weakened by adjusting for socioeconomic and educational confounders. One exception was the association between the natural menopause transition and search speed and concentration, which remained after adjustment for these factors. CONCLUSION: Menopause adversely affects cognitive function, but this effect may be largely explained by premenopausal cognitive function. These findings suggest that common environmental or genetic factors, operating through long-term or lifelong hormonal mechanisms, may influence the timing of natural menopause and lifetime cognitive function.