Barbara B. Sherwin

Effects of estrogen on memory function in surgically menopausal women

The effects of estrogen (E) on memory were assessed in 19 women who required a hysterectomy and bilateral oophorectomy for benign disease. Blood samples were drawn and memory tests were administered before surgery and again after 2 mo of postoperative treatment consisting of either monthly E or placebo (PL) injections. Scores on the immediate and delayed recall of paired-associates stayed at the same level in E-treated women, whereas they decreased significantly pre- to post-operatively in the PL-treated subjects. In the immediate recall of paragraphs, the scores of those given E improved postoperatively compared to baseline; scores remained unchanged in the PL group. No hormonal effects were apparent on the immediate or delayed recall of visual material, delayed recall of paragraphs, or digit span scores. These findings suggest that variations in specific aspects of memory function may occur in surgically menopausal women coincident with changes in plasma estrone and estradiol levels.

Estrogen use and verbal memory in healthy postmenopausal women

OBJECTIVE To assess whether differences in verbal memory might be related to estrogen use in a group of healthy, well-functioning, postmenopausal community-residing women from a broad socioeconomic range. METHODS Healthy postmenopausal women drawn from the general population were given tests of verbal and spatial memory, language, attention, and general spatial skills. The performance of women taking estrogen was compared to that of women from the same population who were not taking any form of estrogen replacement therapy. RESULTS There were no differences between the estrogen users and non-users on any sociodemographic variables. However, the scores of women taking estrogen were significantly higher on tests of immediate and delayed paragraph recall compared to the scores of non-users. No differences were apparent on other tests of cognitive functioning, including tests of spatial memory. CONCLUSION Estrogen appears to have a specific effect on verbal memory skills in healthy postmenopausal women. The clinical relevance of these findings for healthy older women remains to be determined.

Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: A critical review

Although there is now a substantial literature on the putative neuroprotective effects of estrogen on cognitive functioning in postmenopausal women, it is replete with inconsistencies. The critical period hypothesis, posited several years ago, attempts to account for the discrepancies in this literature by positing that estrogen treatment (ET) will protect aspects of cognition in older women only when treatment is initiated soon after the menopause. Indeed, evidence from basic neuroscience and from the animal and human literature reviewed herein provides compelling support for the critical period hypothesis. Although it is not known with certainty why estrogen does not protect cognition and may even cause harm when administered to women over the age of 65years, it is likely that the events that characterize brain aging, such as a reduction in brain volume and in neuronal size, alterations in neurotransmitter systems, and a decrease in dendritic spine numbers, form an unfavorable background that precludes a neuroprotective effects of exogenous estrogen on the brain. Other factors that have likely contributed to the discrepancies in the estrogen-cognition literature include differences in the estrogen compounds used, their route of administration, cyclic versus continuous regimens, and the concomitant use of progestins. This critical analysis attempts to define conditions under which ET may protect aspects of cognition in aging women while also considering the cost/benefit ratio for the treatment of women aged 50-59years. Suggestions for specific future research questions are also addressed.

Estrogenic Effects on Memory in Womena

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)

Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause

The investigation of estrogen and/or androgen administration on physical and psychological symptoms in the surgical menopause was carried out in a prospective, double-blind, crossover design. When patients who received either a combined estrogen-androgen drug or androgen alone were compared with those who received estrogen alone or placebo, energy level, well-being, and appetite were increased (p less than 0.01). The androgen-containing preparations also induced lower somatic, psychological, and total scores on the menopausal index. Superior functioning in the androgen-treated groups occurred in association with higher plasma testosterone levels during the treatment phases (p less than 0.01). These data suggest that reduced levels of circulating testosterone subsequent to bilateral oophorectomy may play an important role in the development of physical and psychological symptoms that are frequent sequelae of this surgical procedure.

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.

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 Womens 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.

ESTROGEN AND COGNITIVE FUNCTIONING IN WOMEN

Abstract 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.

A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive.

Eighty-two women with complaints of moderate to severe premenstrual symptoms were recruited for a double-blind, controlled trial of a triphasic oral contraceptive (o.c.). Subjects made daily ratings of symptoms for at least one baseline cycle and were then randomly assigned to receive either placebo or o.c. for three months. Twenty-three women dropped out of the study (18 o.c., 5 placebo), 13 failed to show prospective confirmation of moderate to severe premenstrual symptoms, and one placebo subject had an anovulatory cycle. Forty-five women with prospectively-confirmed premenstrual changes (20 o.c., 25 placebo) completed the study. Premenstrual breast pain and bloating were significantly reduced with active treatment compared to placebo (p less than 0.03) but there were no beneficial effects of the o.c. over placebo for any of the mood symptoms. Women who received o.c.s reported decreased sexual interest after starting treatment and this effect was independent of any adverse influence on mood.

Estrogen and memory in women: how can we reconcile the findings?

Although several randomized controlled trials (RCTS) of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the RCT, the Womens Health Initiative Memory Study (WHIMS), have reported inconsistent information with regard to the relationship between estrogen and aspects of cognitive function. Although numerous reasons could be offered to explain these discrepancies in research findings, recent evidence from rodent, nonhuman primate, and human studies consistently suggests that one possibility 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 (OVX), provides a window of opportunity for the preservation of memory in females whereas the administration of the hormone following a considerable delay in time after OVX has little or no beneficial effect on cognition. Considering the evidence that, in several organ systems, heightened disease risks accrue to a longer duration of estrogen deprivation in women, it would seem important to determine whether this is also true for brain structure and function in order to protect the quality of life for the considerable number of women who undergo a surgical menopause before their natural menopause had occurred.