The critical period hypothesis: can it explain discrepancies in the oestrogen-cognition literature?

Although there is compelling evidence from small randomised controlled trials and cross-sectional studies indicating that oestrogen helps to protect against cognitive ageing in women, the findings of the large, Women's Health Initiative Memory Study failed to support the earlier findings. The attempt to resolve these discrepancies led to the formulation of the Critical Period Hypothesis which holds that oestrogen has maximal protective benefits on cognition in women when it is initiated closely in time to a natural or surgical menopause but not when treatment is begun decades after the menopause. This article reviews the evidence from basic neuroendocrinology, from animal behavioural studies and from human studies that supports the critical period hypothesis. In view of the promise of this hypothesis and its considerable clinical implications, a direct test of its validity is warranted.

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

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.

Estrogen and cognitive aging in women.

Although several randomized controlled trials of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the Women's Health Initiative Memory Study, have failed to confirm these findings. One critical difference between studies that found a protective effect of estrogen on memory and those that did not is that, in the former studies, treatment with estrogen began at the time of menopause and in the latter studies, it was first administered many years after the menopause had occurred. Recent evidence from rodent, nonhuman primate, and human studies consistently suggests that the timing of the initiation of estrogen treatment with regard to the menopause may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy, provides a window of opportunity for the protection of memory in females whereas the administration of the hormone following a considerable delay in time after ovariectomy or following a natural menopause has little or no beneficial effect on cognition.

Oestrogen and cognitive function throughout the female lifespan.

Evidence that oestrogen helps to maintain verbal memory in women comes from several sources. Studies that have tested cognitive functioning at different phases of the menstrual cycle have found few differences, perhaps because oestrogen levels are sufficiently high, albeit variable, during all cycle phases. Experimental studies in postmenopausal women have generally found a protective effect of oestrogen, specifically on verbal memory. Results of several large, longitudinal studies that have become available recently have also demonstrated that women who were oestrogen users performed better on certain tests of cognitive function than non-users of similar age. On the basis of this body of evidence, it is possible to conclude that oestrogen may attenuate or prevent the decline in aspects of memory that occur with normal ageing in women.

Mild cognitive impairment: potential pharmacological treatment options.

Both mild cognitive impairment and age-associated memory impairment are terms used to describe memory decline in otherwise healthy, intellectually intact individuals aged older than 50 years. It is estimated that up to 38% of the middle-aged and older population fulfill diagnostic criteria for this condition. Although the memory deficits observed in these individuals are fairly mild, they can interfere with day-to-day functioning. This article presents a review of the types of memory decline observed in older people, the diagnostic criteria used to define memory decline, the physiological and morphological brain changes that accompany aging, and the potential pharmacological treatment options, focusing on agents that have been evaluated in mildly cognitively impaired or normal older populations.

Higher levels of plasma estradiol and testosterone in healthy elderly men compared with age-matched women may protect aspects of explicit memory.

OBJECTIVE: To assess longitudinally the relationships between plasma levels of estradiol (E2) and free testosterone (T) and cognitive functioning in elderly men, women who use estrogen, and women who do not use estrogen. DESIGN: At two test times 18 months apart (time 1 and time 2), men (time 1, n = 31; time 2, n = 23), women who were using estrogen (time 1, n = 14; time 2, n = 10), and women who were not using estrogen (time 1, n = 41; time 2, n = 27), whose average age was 72.1 and 73.4 years at time 1 and time 2, respectively, were administered a battery of neuropsychological tests that measured verbal memory, visual memory, concentration and attention, language fluency, and semantic memory. Plasma levels of E2 and free T were assessed by radioimmunoassay. RESULTS: The men had higher free T levels than both groups of women at both test times. Although women who were using estrogen had higher E2 levels than those of the men and of the women who were not using estrogen, the men's E2 levels were also significantly higher than those of the women who were not using estrogen. Moreover, the women who were using estrogen and the men had higher Forward Digit Span scores compared with the women who were not using estrogen at both test times, and women who were using estrogen had higher Backward Digit Span scores than those who were not using estrogen. Both groups of women performed better than the men on the Category Retrieval Test (verbal fluency). The performance of women who were using estrogen on the Delayed Selective Reminding Test (long-term rote memory) improved over time compared with that of the men and of the women who were not using estrogen. CONCLUSIONS: These findings raise the possibility that higher E2 levels in elderly men and in women who use estrogen may protect against some declines in explicit memory with normal aging.

Relationships between mood and estradiol (E2) levels in Alzheimer's disease (AD) patients.

This study investigates the relationship between mood and estradiol (E2) levels and assesses the prevalence of mood symptoms in Alzheimer's disease (AD) patients compared to healthy elderly controls. Fifty-two AD patients (26 men, 23 estrogen non-using women and three estrogen-using women), mean age 76.2 years, were recruited and assessed with the Geriatric Depression Scale (GDS), a test of mood, and a radioimmunoassay measure of E2 levels at the time of testing. The AD patients were compared to a control group of age and gender-matched healthy elderly men and women estrogen-users and non-users. No differences were found between the AD patients and the controls in overall E2 levels, but, as expected, the women estrogen-users in both the AD and control groups had higher E2 levels than the men and the female estrogen non-users. Both groups of men had higher E2 levels than the estrogen non-using women. There was a significant negative correlation between E2 levels and GDS scores in the full sample, which was particularly strong in the estrogen-using women. This indicates that those subjects with higher E2 levels had less mood symptomatology. Overall, mood scores in the AD patients were higher than in the healthy controls, indicating higher levels of depressive symptomatology; the highest depression scores occurred in the AD women who were estrogen non-users. This suggests that depressive symptoms are common in AD patients, and that women with AD who are not taking estrogen replacement may be especially vulnerable to depression.

Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women.

At test times 18 months apart (Time 1 and Time 2), men (n Time 1 = 31, Time 2 = 23), women estrogen-users (n Time 1 = 14, Time 2 = 10), and women estrogen non-users (n Time 1 = 41, Time 2 = 27), whose average age was 72.1 and 73.4 years at Time 1 and Time 2, respectively, were tested with a battery of neuropsychological tests measuring verbal memory, visual memory, concentration/attention, language fluency and semantic memory. Plasma levels of CRT and DHEAS were assayed by radioimmunoassay at both test times. The men had higher DHEAS levels than both groups of women at both test times (p < 0.001) and also had a higher DHEAS/CRT ratio compared to the estrogen non-users (p < 0.05). Although there were no group differences in CRT levels at either time, CRT levels increased in the estrogen non-using women from Time 1 to Time 2 (p < 0.001). Subjects with lower CRT levels performed better than those with higher levels on several tests of declarative memory (p < 0.05). Men and estrogen-users had higher Digit Span scores compared to female estrogen non-users at both test times (p < 0.01), and women estrogen-users also had higher Backward Digit Span scores than non-users (p < 0.05). Both groups of women performed better than men on Category Retrieval (p < 0.01). These findings suggest that higher CRT levels in elderly men and women are associated with poorer explicit memory functioning; however, these results failed to provide any evidence that DHEAS is protective against declarative memory decline with aging.

Can estrogen keep you smart? Evidence from clinical studies.

OBJECTIVE: To review and critically analyze the biological plausibility of and the clinical empirical evidence concerning a link between estrogen levels and memory in women. DATA SOURCES: MEDLINE search of the literature published from 1980 to 1998. Studies published between 1952 and 1980 that were known to the author were also included. STUDY SELECTION: Sixteen prospective, placebo-controlled studies in humans. DATA SYNTHESIS: Most of the studies that used neuropsychological tests with known reliability and validity found that estrogen maintained aspects of memory in women. CONCLUSIONS: Estrogen specifically maintains verbal memory in women and may prevent or forestall the deterioration in short- and long-term memory that occurs with normal aging. There is also evidence that estrogen decreases the incidence of Alzheimer disease or retards its onset or both.

Relationships between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer's disease patients compared to healthy controls.

Fifty-two age-matched Alzheimer's disease (AD) patients (26 men, 26 women), mean age 76.2 years, were assessed with the Rivermead Behavioural Memory Test, a test of everyday memory, coincident with the measurement of plasma cortisol (CRT) and dehydroepiandrosterone sulfate (DHEAS) via radioimmunoassay. The AD patients were compared to a control group of age- and gender-matched healthy elderly men and women. No differences were found between the AD patients and the controls in DHEAS or CRT levels, or in the DHEAS/CRT ratio. There were no gender differences in DHEAS or CRT levels, or in the DHEAS/CRT ratio in subjects with AD. However, AD patients with higher levels of DHEAS scored better than those with lower levels on the subtests of Remembering a Name associated with a picture, Digit Span Total and Forward, and the Mini Mental Status Exam. AD patients with higher CRT levels performed worse on Delayed Route Recall than those with lower levels. These findings suggest that AD patients with higher endogenous levels of DHEAS may perform better on some memory tasks than those with lower levels, while AD patients with lower levels of CRT may perform better than those with higher CRT.

Progestogens used in menopause. Side effects, mood and quality of life.

Progesterone receptors are found in many of the same brain areas as estrogen receptors, including the hypothalamus and limbic system. The limbic system, particularly the amygdala, plays a prominent role in regulating emotion and mood. Progestogens decrease brain excitability, whereas estrogens increase it. This explains, in part, why women with epilepsy have a higher frequency of seizures during the late follicular and ovulatory phases of the menstrual cycle than during the luteal phase. In addition, progesterone has been shown to have profound anesthetic properties and to increase the concentration of monoamine oxidase (MAO), the enzyme that catabolizes serotonin in the brain), whereas estrogen decreases MAO, thereby increasing the concentration of serotonin. The purpose of this paper is to review the extant research regarding these biologic effects of progestogens on brain function.

Cognitive assessment for postmenopausal women and general assessment of their mental health.

Mechanisms of action of estrogen on brain structure and function provide biological plausibility for the purported effects of this steroid hormone on aspects of cognition in women. Prospective experimental studies and observational studies indicate that estrogen helps maintain verbal and, possibly, visual memory in women. A suggested battery of neuropsychological tests is presented while caveats concerning possible experimental confounds in studies of estrogen and memory such as depression and the concomitant administration of progestins are discussed. The use of hormone replacement therapy (HRT) in postmenopausal women must also consider the risks and benefits of such treatment for each individual woman.

Steroid hormones, memory and mood in a healthy elderly population.

Men (n = 31), women estrogen-users (n = 14), and women estrogen non-users (n = 41), whose average age was 72.1 +/- 5.6 years, were tested with a battery of psychological tests measuring verbal memory, visual memory, concentration and attention, language fluency and semantic memory, and mood. Plasma levels of testosterone (T), estradiol (E2), cortisol (CRT) and dehydroepiandrosterone-sulfate (DHEAS) were assessed by radioimmunoassay. The ratio of DHEAS to CRT was calculated to determine it's relationship to memory functioning. The men had higher T and DHEAS levels than both groups of women. Women estrogen-users had higher E2 levels than both men and estrogen non-users and the men had higher E2 levels and a higher DHEAS/CRT ratio than the estrogen non-users. There were no group differences in CRT levels. Men and estrogen-users had higher total (p < .01) and forward (p < .001) digit span scores compared with non-users. Women estrogen-users also had higher backward digit span scores than non-users (p < .05), while both groups of women performed better than men on category retrieval (p < .01). The implications of these findings with respect to hormonal influences on memory in elderly men and women are discussed.

Use of combined estrogen-androgen preparations in the postmenopause: evidence from clinical studies.

This article reviews the effects, on clinical symptoms, such as energy level and aspects of sexual functioning in postmenopausal women, of adding testosterone to an estrogen replacement regimen. The efficacy of combined estrogen-androgen preparations on bone density and lipoprotein lipid metabolism is also reviewed. Clinical recommendations for use of combined therapy are described with respect to specific symptoms.

Estrogen and cognitive functioning in women.

Findings from basic neuroscience have elucidated mechanisms of action of estrogen on the structure and function of brain areas known to be critically involved in memory. Controlled clinical studies of the administration of estrogen to postmenopausal women have found that estrogen enhances verbal memory and maintains the ability to learn new material. These findings are supported by those from investigations of healthy, elderly, women and by results of a study in which younger women received a gonadotropin releasing-hormone analog that suppressed ovarian function. The specificity of the estrogenic effect on cognitive functions is consistent with known sex differences in cognitive abilities and suggests that, in adulthood, estrogen serves to activate neural pathways established under the influence of this steroid hormone during prenatal life.

Estrogen effects on cognition in menopausal women.

There is now considerable evidence from basic neuroscience that estrogen influences aspects of brain chemistry and brain morphology known to be important for memory functions. Prospective, controlled studies of surgically and naturally menopausal women demonstrated that exogenous estrogen enhanced short- and long-term memory and the capacity for learning new associations, whereas visual memory was unaffected. Healthy, 65 year-old women who took estrogen also performed significantly better than estrogen-nonusers who were matched for age, socioeconomic status, and years of formal education. Finally, in 32-year-old women with uterine myomas, a gonadotropin-releasing hormone agonist (GnRH-a) resulted both in ovarian suppression and in a decrease in verbal memory which was reversed by addition of estrogen to the GnRH-a treatment. Taken together, these findings suggest that estrogen helps to maintain verbal memory and enhances the capacity for new learning in women, whereas other cognitive functions such as verbal memory are seemingly unaffected by this steroid hormone.

"Add-back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri.

Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause.

Estradiol is related to visual memory in healthy young men.

The influence of testosterone and estrogen on memory was investigated in 33 healthy young men. Tests of visual memory, visuospatial ability, verbal memory, and attention were administered, and circulating levels of estradiol and free testosterone were measured. Participants with high levels of estradiol performed better on 2 measures of visual memory than did those with normal but lower levels. There were no differences between individuals with high and low levels of testosterone on any cognitive measure. These results support the contention that estradiol influences memory in young men.

Hormones, mood, and cognitive functioning in postmenopausal women.

Findings from basic neuroscience have provided information on the effects of estrogen on brain morphology and chemistry that explain how this sex steroid may influence brain function. The clinical literature shows that estrogen enhances mood and specific aspects of cognitive functioning in postmenopausal women. There is also evidence that estrogenic effects on various psychological functions are dissociable and specific. Although several recent epidemiologic case-control studies have suggested a protective effect of estrogen against Alzheimer disease, these findings need to be verified by prospective, controlled investigations.

Estrogenic effects on memory in women.

Sufficient evidence now exists to support the contention that estrogen influences cognitive functioning in women. Moreover, the data strongly suggest that estrogen exerts a specific and not a global effect on cognitive functions. Whereas estrogen enhances and/or maintains aspects of verbal memory, it is without effect, or possibly even has a negative influence on spatial memory. Indeed, there is some preliminary evidence that progesterone may enhance visual-spatial skills in women but this needs to be confirmed. Estrogen also exerts a positive effect on sexually dimorphic cognitive skills in which females typically excel such as verbal articulation and fine motor skills. While the weight of the evidence supports the above conclusion, findings across studies are not entirely consistent. Some of the methodological problems that weaken these studies include generalizing from one or two cognitive tasks to the entire realm of cognitive functions, neglecting to assay plasma levels of estradiol to confirm cycle phase or compliance with hormone administration and neglecting to consider the differential availability to the brain of the various estrogen preparations and the effects of different routes of administration. Although, for the most part, the menstrual cycle studies and the postmenopausal studies in healthy women show that estrogen maintains verbal memory, the effect size is modest. There is no reason to believe, for example, that verbal memory is truly impaired in women during phases of the menstrual cycle marked by low levels of estrogen. Nor are 45-year-old untreated, surgically menopausal women clinically impaired to any degree that affects their daily functioning in the real world. In both cases, however, decrements in performance occur reliably in the laboratory. This raises the issue, therefore, of the clinical meaningfulness of these findings. One way to address the clinical relevance of the relationship between estrogen and memory and thus, on cognitive functioning of the brain, is to examine what is known of estrogenic effects on other physiological systems where we already have substantial information. For example, the vast majority of women experience bone loss following the menopause and many develop osteopenia (bone density more than two standard deviations below mean peak bone mass levels) which is asymptomatic. Then, with advancing age, some women with osteopenia develop osteoporosis, predisposing them to fractures following minimal trauma. It has been estimated that 40 per cent of women who live to age 80 will develop spinal fractures and 33 per cent of women who live to age 90 will experience a hip fracture.(ABSTRACT TRUNCATED AT 400 WORDS)