Table of Contents

• Overview and Objectives
• Introduction
• Estrogen and the Brain
• Cognition
• Alterations in Mood
• Depression
• Alzheimer's Disease
• Nursing Implications: Mood, Cognition, and Alzheimer's Disease
• Colon Cancer
• Emerging Trends
• Summary
• Case Studies
• Patient Handout

Overview

• outlining the action of estrogen in the brain
• discussing the implications of menopause and mood/cognition changes
• explaining the risk of Alzheimer's disease after menopause
• describing the benefits of estrogen in terms of Alzheimer's disease
• analyzing emerging data on benefits of estrogen use as it relates to vision disturbances, Parkinson's disease, diabetes, osteoarthritis, and colon cancer.

Objectives

1. state the actions of estrogen in the brain
2. describe how menopause contributes to cognition and mood changes
3. define the risk of developing Alzheimer's disease
4. discuss the potential benefits of estrogen in terms of Alzheimer's disease
5. compare depression and dementia and their impact on caregivers
6. explore 4 new areas in which estrogen research is just beginning to emerge
7. analyze the nursing role in maximizing menopausal health

Introduction

It is important for nurses to stay abreast of research advances as science continues to uncover and define the benefits of HRT. It is also particularly valuable for nurses to be sensitive to mental health issues, such as mood changes or depression, that can surface at the time of menopause. Such issues often go unrecognized or unaddressed and are sometimes dismissed by women as being "part of daily life," or "all in my head." Menopause represents an important time for women to reassess their health, their lifestyle, and their expectations for the future. As front-line health professionals, nurses can help menopausal women weigh the risks and benefits of HRT and make a decision that is appropriate for them.

Estrogen and the Brain

• stimulates the expression of factors that promote neuronal growth within the central nervous system (CNS)
• protects neurons from ß-amyloid toxicity (a feature of Alzheimer's disease)
• stimulates the regeneration of axons and synapses
• maintains viability and survival of neurons, thus preserving the information-processing capability and storage capacity of a brain cell
• increases regional cerebral blood flow
• stimulates production of the neurotransmitters acetylcholine and serotonin

The actions of estrogen on neurotransmitter systems are specific, that is to say, estrogen is not a general "tonic." Instead, estrogen can be directly linked with certain systems and their domains, or areas of influence (Table 1).

Table 1

Cognition

Normal cognition can also be affected by the estrogen loss associated with menopause. The most common complaints are memory loss and difficulty in concentrating. The first reports of estrogen benefiting cognition demonstrated that estrogen plays an important role in the maintenance of short-term memory in women.(8) The study shown in Figure 1 involved surgically menopausal women who were tested on immediate paragraph recall, which is considered a measure of short-term memory.(9) Estrogen treatment after surgery produced higher scores than did placebo.

Figure 1

A recent study, however, found that the benefits of estrogen extend beyond the domain of verbal memory. Cognitive performance was evaluated among 727 healthy menopausal women.(10) The women who used estrogen scored higher on standardized tests of memory (shown in Figure 2), language, and abstract reasoning at baseline, and their verbal memory performance improved slightly at the end of 2.5 years' follow-up. These findings were independent of ethnicity, education, and age, and apolipoprotein E status (a risk factor for Alzheimer's disease).

Figure 2

Alterations in Mood

It is important for nurses to make an effort to help patients sort out any underlying causes of psychological symptoms that surface with the menopause. Some symptoms may stem from existing stressors in the patient's personal life. Women of lower socioeconomic status are more likely to have more psychological symptoms around the time of menopause.(8) And a number of other factors contribute to mood changes including:

• negative attitudes toward the menopause
• poor social support
• poor marital relations
• stressful life events
• recent bereavement

DEPRESSION

In general, the literature evaluating the incidence of depression surrounding menopause shows conflicting incidence rates.(13) However, a recent study adds substantially to evidence for a link between depression and menopause.(14) This study reported current depression scores for 363 women aged 40 to 60 years who attended a women's primary care clinic. Perimenopausal women were twice as likely to have significant depressive symptoms (elevated scores assessed by the Community Epidemiology Scale), as were middle-aged premenopausal women (odds ratio 2.(0), P = 0.(0)37). This difference held when the study was controlled for a history of depression. The percentage of women with depressive symptoms was the same for perimenopausal and postmenopausal women. It is noteworthy that hot flushes were positively correlated with elevated depression scores.

The role of estrogen in depression is frequently debated as well. The answer to whether or not estrogen is an antidepressant differs depending on the origin of the study. Some studies of major depressive disorder (generally conducted by psychiatrists) have shown no benefit from estrogen monotherapy.(15) On the other hand, there are perhaps 30 studies from the primary care/women's health setting showing estrogen to be an effective stabilizer of mood that can improve a sense of well-being.(15)

What is apparent is that estrogen has multiple neuromodulatory effects, similar to the neuro-pharmacologic actions of antidepressant medications. These effects include:(16)

• increased serotonin synthesis and postsynaptic responsiveness
• increased norepinephrine turnover
• a mixed effect on dopamine and endorphins

Because of estrogen's activity in the CNS, it may modulate mood in such a way as to reduce depression.(12) There are also anecdotal clinical observations that suggest an estrogen/antidepressant agent synergy, but confirmatory studies are lacking

Alzheimer's Disease

Table 2

The number of persons over age 85 is now the fastest growing segment of the US population. The number of Americans with AD will double by 2030, and the number of people affected will reach 14 million by 2050. With this increase, there will be a significant increase in the cost of caring for this population beyond the 1990 figure of $100 billion.(17)

The prevalence of AD is greatest in those over age 85 (Figure 3).(17) After the age of 65 or 70, the number of individuals with AD doubles every 5 years, so that by the age of 85 as much as 50% of the population may be affected.(18-20) An additional 20% may have the neuropathologic plaque changes of AD in the absence of clinical dementia.(21) This exponential increase in the apparent increase in AD is seen across racial and ethnic groups and is assumed to be intrinsic to the aging process.

Figure 3

Both in terms of prevalence and incidence, AD is a major health issue for women.(20,22) Women comprise 72% of the population over 85 years of age, and roughly half of this group has Alzheimer's disease. Not only do women constitute a greater proportion of the older population, but AD is expressed earlier in women than in men. This may be related to the estrogen loss that occurs with menopause.

Effect of Estrogen on AD

The best evidence that relates estrogen deficiency to Alzheimer's disease comes from several epidemiological studies. The 5 independent studies in the relative risk (RR) scale in Figure 4 consistently demonstrate a 40% to 60% reduction in the risk of AD in women who have taken ERT.(23-27) This risk reduction supports the role of estrogen in preventing or delaying AD. Relative risk is defined in Table 3.

Figure 4

Table 3

These 5 studies are large epidemiologic studies that provide significant data about estrogen and Alzheimer's disease. In particular, the study that originates with the Leisure World Cohort involved observation of 8877 women over a 14-year period (1981-1995).(24) Using a subset of these individuals, a case-control study of Alzheimer's disease evaluated the impact of estrogen replacement. Of the 3760 women who died in the 14-year period, 248 were women with the diagnosis of AD on a death certificate. These women were the cases. Each case was paired with 5 age-matched controls who died within 1 year of the case, but who did not have diagnosed dementia. The risk of Alzheimer's disease and related dementia was significantly reduced in estrogen users. This reduction was dependent on the dose of conjugated equine estrogen (CEE) used and the duration of exposure to estrogen (Table 4 - odds ratio can be interpreted similarly to relative risk). The longer a woman takes estrogen, and the higher the dose, the greater the protection from AD.

Table 4

In addition, there are 3 small clinical studies that examine the effects of estrogen administration in an elderly population of women. They do not provide the definitive information that epidemiological studies do, and some of them are old.But they are suggestive of trends and serve as a guide for future research. Although these patients were not necessarily diagnosed with AD, the studies evaluate memory and cognition, which often decline in the AD population. One study involved 30 elderly residents of a "home for the aged" whose mean age was 75 years.(28) The women were randomized to treatment with 2 mg of estradiol benzoate IM every week or placebo in an IM vehicle every week for 12 months. The Wechsler memory scale was used as the outcome measure. There was a significant improvement in memory over baseline for the first 12 months with treatment and a decline in memory with placebo. Because baseline performance was impaired, many of these women may have had AD. Although the improvement in memory was modest in magnitude, it is equivalent to about 1.5 years of AD progression. The clinical implication about estrogen's effect in this study was that it might delay the progression of the disease.

Another study involved 50 elderly women in a "home for the aged" who were randomized to treatment with CEE 0.625 mg daily or placebo for 36 months.(29) Many of these women may have had AD. Outcome measures consisted of a standardized interview assessing communication and self-care abilities. The interviewers were blinded in terms of treatment. Treatment with estrogen produced a progressive improvement over the first 12 months followed by a decline (Figure 5). The net effect of treatment was a delay in progression of cognitive decline. This small clinical study again suggests that estrogen therapy may allow the maintenance of independence for several additional years.

Figure 5

A third small clinical study in which the subjects actually had mild to moderate AD involved 30 women, 15 of whom were treated with CEE 0.625 mg daily for 5 months.(30) Psychometric evaluations were performed every month with the Hasegawa Dementia Scale (HDS). Women who were treated with estrogen sustained an improvement in HDS scores. The study suggests that estrogen therapy may improve cognitive function or slow the rate of cognitive decline in patients with established AD.

Estrogen therapy showed unexpected benefit in a reanalysis of the pivotal tacrine trial that lead to the approval of this drug for the treatment of AD.(31) Tacrine is a cholinesterase inhibitor. The study involved a subgroup of women who were receiving estrogen at the time of randomization to tacrine. Contrary to what would have been expected, tacrine alone had no significant effect on cognitive function. Instead, only women receiving ERT concurrently with tacrine had a beneficial, and significant, response (as measured by the cognitive component of the Alzheimer's Disease Assessment Score test). This study has some important implications for other cholinesterase inhibitors that are being investigated for the treatment of AD. It is possible that such agents may also require the concomitant administration of estrogen for their efficacy.

How these observations on estrogen therapy might translate into the clinical setting was explored in a small double-blind, placebo-controlled study of 20 subjects. Treatment consisted of estrogen (CEE) 0. 625 mg daily for 9 months cycled every third month with progestin (medroxyprogesterone acetate) 5 mg for 13 days.(32) The outcome measure was the Clinician Interview Based Impression (CIBI), in which the patient and the caregiver are interviewed by a clinician blinded to treatment and objective measures of cognitive function. Nine domains of behavior and cognitive function are assessed for change. This measure is designed to detect clinically relevant changes in function as opposed to statistically measurable changes that may not translate into clinically significant changes. Of those subjects on active drug, 80% showed clinical improvement, whereas none of the subjects on placebo showed improvement (Figure 6).

Figure 6

Finally, an additional study is noteworthy because all of its 1124 subjects were free of AD at baseline and were followed for 1 to 5 years.(26) The curves in Figure 7 show the percentage of the study population that was free of disease at certain ages. Women who took estrogen for more than 1 year experienced a dramatic delay of AD onset. But even short-term estrogen therapy produced a delay. This group of women averaged 4 months of estrogen therapy and most likely took the medication to control menopausal symptoms such as hot flushes. This raises the question of how brief exposure to estrogen for treatment of hot flushes could influence AD expression 20 to 30 years later.

Figure 7

One hypothesis to explain such an estrogen effect links the hot flush with an irreversible loss of neurons. Thus, women with a history of untreated hot flushes will have a decrease in neuronal reserve as they enter their 70s and 80s and are therefore more likely to express AD at an earlier age.

There is, in fact, some support for the concept that hot flushes are associated with neuronal loss from a study that involved women who required a hysterectomy and bilateral oophorectomy for benign disease.(33) Their cognitive function was assessed prior to surgery and 2 months later. On tests of verbal memory there was a significant, negative association between the selected domain of cognitive function and the severity of hot flushes. Moreover, these changes in cognitive function could not be explained by changes in depressive symptomatology, anxiety, or insomnia.

It is hypothesized that with the loss of estrogen at the time of menopause, there is a decrease in estrogen-dependent glucose transport into the CNS, thereby resulting in a selective loss of neurons within the hippocampus. This region of the brain is related to memory and is involved in AD changes. Should the relationship between estrogen, glucose transport, and the hot flush prove to be significant, it may be important to examine other perimenopausal therapeutic alternatives for their effect on the vasomotor symptom of hot flushes. For example, raloxifene, the newest selective estrogen receptor modulator (SERM), seems to be associated with an increased incidence of such hot flushes.(34) Roughly 30% of women have experienced hot flushes with raloxifene therapy of 60 mg.

Summary of AD Treatment Options

There are currently few alternatives for treating AD. Cholinesterase inhibitors, tacrine and donepezil, affect the symptoms of AD but not the disease process, and the efficacy of these drugs may require a synergistic interaction with estrogen, which enhances the production of acetylcholine.(31) Epidemiologic evidence consistently indicates that nonsteroidal anti-inflammatory drugs delay the expression and the progression of AD.(35,36) Also, vitamin E, an antioxidant, slows the progression of AD.(37)

Nursing Implications: Mood, Cognition, and Alzheimer's Disease

• energy levels
• sleep patterns
• weight and appetite changes
• level of interest in activities and daily life
• concentration
• memory
• sensation of a "short fuse"
• frustration

It is also valuable for patients to know that depression is often one of the first signs of AD. Depression and symptoms of early dementia can occur simultaneously, but the relationship between the 2 disorders is not clear. It has been suggested that an onset of depression late in life, with no prior history, is a risk factor for the development of Alzheimer's disease.(38) Conversely, depression can also present as a clinical pseudodementia or depression with cognitive impairment that, unlike AD, resolves with treatment. When depression and dementia overlap, they contribute to lowered cognitive function and performance. Correction of the depression can improve the cognitive dysfunction to some extent.(39,40)

The fact that depression and dementia share similar neurovegetative symptoms such as psychomotor changes, loss of interest, or insomnia, can complicate diagnostic efforts. Clarification often results after taking a careful history of the problem and comparing several characteristics of these disorders listed in Table 5. Both the patient and caregiver should be interviewed during the assessment. Several studies have reported that patients with dementia are poor raters of their symptoms and underestimate the severity of their condition.(41) Depression is more common in the mild to moderate stages of Alzheimer's disease and is less problematic in the late stages.(42)

Table 5

Differentiating between dementia and depression is critical in older patients, and it can also provide valuable information for menopausal women who assume caregiving roles for older relatives.

Menopausal Women as Caregivers

Caregiving has a dramatic influence on the physical, emotional, social, and financial resources of an individual. A number of studies have documented the tremendous hardship placed upon caregivers and the sequelae of physical and emotional disorders that caregivers develop.(43-48) These studies also emphasize that the personal resources of the caregiver, as well as the existing social support network, determine how the "burden" or responsibility of caregiving is perceived.

It is helpful for caregivers to know that the course of dementing disorders can be significantly improved by a number of pharmacological agents, such as estrogen replacement therapy. This knowledge provides caregiving women the means for greater control over an illness previously thought untreatable. A sense of mastery or control, along with the social support networks suggested by nurses, can contribute to the well-being of caregivers.(49-51)

Colon Cancer

The concept that postmenopausal HRT may decrease the risk of colorectal cancer has received considerable attention, even though estrogen has no indication for this use. Some 20 epidemiologic studies have been published that examined this relationship.(54) The majority of these suggest an inverse, protective effect for HRT, particularly with current use. For the studies shown in Figure 8, current/recent use was defined as use within 1 year of colorectal cancer diagnosis. These trials, including 2 meta-analyses, show a clear beneficial effect for estrogen on colorectal cancer.(55-66)

Figure 8

Although the precise mechanism for how estrogen might reduce colon cancer risk is unknown, it has been hypothesized that it affects bile acid metabolism or promotes tumor suppressor activity through estrogen receptors.(54) Around the time of menopause, colon cancer and preventive measures, including HRT, should be part of the discussions between women and nurses (Table 6). Counseling should include the American Cancer Society recommendations for annual digital rectal exam (DRE) and fecal occult blood testing as well as a flexible sigmoidoscopy every 5 years or colonoscopy every 10 years.

Table 6

Emerging Trends

Vision: Age-Related Macular Degeneration

Deterioration in visual acuity and dryness were the 2 most common complaints of the 19 reported. Ninety-eight women underwent ophthalmic examination and received cyclical HRT for 3 months. Most of the women who were followed reported substantial improvement or complete freedom from their ocular complaints by the end of 3 months. Moreover, physician examination provided objective evidence of improvement in 2 parameters: increased lacrimal fluid, and improved convergence and fusion (which is indicative of improved visual acuity).

Studies are uncovering other possible benefits from estrogen replacement therapy. For instance, age-related macular degeneration (AMD) may be reduced by estrogen administration.(68) This disease is the leading cause of legal blindness in the United States, accounting for as many as 60% of all new cases. Early-stage AMD is common in the population, and patients are usually asymptomatic. About 17% of the population between the ages of 43 and 86 years have this type of AMD. This figure rises to 35% when the >75 population is isolated.

The prevalence of late-stage, or exudative, disease increases after the age of 75 years (Figure 9), and this increase is more significant in women than in men. Late-stage disease, both the wet and dry types, affect 7% of the elderly population.(69) It is the late-stage disease that most often leads to blindness. The pathogenesis of the disease is poorly understood, although there is a high association between AMD and smoking. There is no medical treatment, and surgical treatment in the form of photocoagulation is effective in only a small percentage of patients with the wet type of the disease.

Figure 9

There is some evidence that there is an association between menopause and AMD. In the Rotterdam study, women with a younger age at menopause had a 90% increased risk of exhibiting signs of late AMD compared to those whose age at menopause was older.(70) The data in Table 7 are from a large case-controlled study of end-stage disease, and these data suggest that HRT reduces the risk of developing AMD.(68) Another study also suggested that ERT/HRT produces a very small reduction that is not statistically significant for early and late stages of AMD.(71) There was a 1% to 4% reduction of AMD per year of ERT/HRT depending upon the severity level of AMD.

Table 7

Parkinson's Disease

Given estrogen's effect on the CNS, research efforts are just now beginning to investigate Parkinson's disease (PD) and HRT. PD is a neurodegenerative disorder affecting the dopamine-producing cells of a specific region of the brain: the substantia nigra (Table 8).(72-75) PD is characterized by 4 cardinal features: tremor at rest, rigidity, bradykinesia or slowness of movement, and postural instability. Patients may have some or all of these features. Over time, there is gradual progression of the motor symptoms of PD. In addition, long-term complications of treatment, which may include motor fluctuations, dyskinesia, psychosis, and dementia, develop in the majority of patients.

Table 8

The mean age of onset of PD is 58 to 62 years, and the incidence of this disease increases with age (Figure 10).(76) Most epidemiological studies reveal a prepond-erance of PD cases in men; specifically, studies suggest a 60% to 40% split between men and women.

Figure 10

PD becomes clinically evident only when the majority of substantia nigra neurons are lost. It is not known precisely when this process begins, although many believe that neurodegeneration starts 10 or more years prior to the emergence of symptoms. For women, this means neurodegeneration often begins premenopausally, at the time when women might reasonably consider beginning HRT for its benefits. Thus, attention has recently focused anew on how estrogen affects PD.

Case studies from the last 20 years that examined the effect of estrogen on PD and other dopamine-related disorders are contradictory. They report mixed effects for estrogen, but the abundant basic science literature reveals numerous mechanisms supporting a positive effect of estrogen on dopamine neurotransmission.(77-81) Estrogen may work directly as a neuroprotective agent on the dopamine neurons. It may also increase sensitivity to dopamine as well as decrease dopamine reuptake.

Several small studies suggest that estrogen has a direct beneficial effect on the pharmacokinetics of levodopa, which is the mainstay of treatment for PD.(82-86)

Clinically, estrogen administration might prove eventually to have a beneficial effect on levodopa metabolism, which could increase the efficacy of levodopa and reduce the dosage of levodopa needed.

One recent study found that estrogen administration was associated with less severe Parkinson's symptoms.(87) It included only women who had symptoms of presumed PD for <5 years and who were not yet taking levodopa at the time of their first visit. The effect of estrogen on disease severity was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). Thirty-four of the women had used estrogen at some time and 104 had never received estrogen. The investigators found a positive and significant association between estrogen use and lower symptom severity in women with early PD (Figure 11).

Figure 11

About 40% of PD patients develop dementia, and the majority of patients develop some degree of cognitive dysfunction. In a clinical study using a battery of cognitive tests to evaluate female patients with PD, estrogen had an impact on cognitive function. All of the women, regardless of ERT use, had similar ability to learn new verbal material, but ERT use was associated with better retention of that learned material.(88) Another study found that estrogen reduced the development of dementia among women with Parkinson's disease.(89) Although the data on estrogen and PD are preliminary, there is sufficient suggestion of a beneficial effect to warrant further study.

Diabetes

Another area in which preliminary evidence is just beginning to emerge is the effect of estrogen on diabetes. As the population ages, the economic and sociological impact of diabetes, particularly type 2 diabetes, will increase dramatically. Approximately half of all diabetes cases occur in people over the age of 55.(90) And by the year 2015, 45% of all women in the United States will be 45 years of age or older.(91) The makeup of the US diabetes population emphasizes this point: 5% to 10% have type 1; 90% to 95% have type 2; and 2% to 5% have gestational diabetes. Almost 6% of the US population is affected by diabetes, although roughly 1/3 of those with the disease remain undiagnosed.(90) Current estimates of the total yearly cost of diabetes, both direct and indirect, are $98 billion.(90) Moreover, the complications of diabetes are significant (Table 9).

Table 9

One of the most devastating consequences of diabetes is its contribution to cardiovascular disease. As many as 75% of deaths in individuals with diabetes are caused by heart disease or stroke.(92) The Nurses' Health Study revealed that women with diabetes have a 5-fold higher risk of coronary heart disease than do nondiabetic women.(92,93) Furthermore, diabetes somehow negates the protective effect that being female usually has on the risk of developing heart disease.(91,92,94)

The effect of diabetes on cardiovascular mortality is dramatically illustrated in this 24-year follow-up of a large cohort of patients (Figure 12). The study included diabetic men and women who were diagnosed between the ages of 35 and 64 years and who came to the Joslin Clinic soon after diagnosis. They were compared to a group of similarly aged nondiabetic participants in the Framingham study.(95) The increased coronary artery disease (CAD) mortality among diabetic patients, which is already evident in the first 3 years of observation, increased significantly as time progressed.

Figure 12

Recent investigations have provided a wealth of information about the effects of hormone replacement therapy on disease prevention in predominantly healthy women. However, because women with diabetes have been systematically excluded from the majority of early prospective trials of ERT/HRT, scant information is available about the effects of estrogen in this population.

One study has found a decreased risk of myocardial infarction (MI) in diabetic women currently taking HRT. Case subjects were all postmenopausal women with treated diabetes who had had a fatal or nonfatal MI.(96) Controls were treated diabetic postmenopausal women without prior MI. History of ERT/HRT use was obtained from computerized pharmacy records. The relative risk of MI for current estrogen users was 0.51 (0.22-1.15), which represents a 49% reduction. The relative risk for MI declined with each additional year of estrogen use. But such protection was completely lost among women who had discontinued estrogen.

Studies are now beginning to look at how estrogen affects the management of diabetes itself. A prospective trial of 18 women evaluated the effect of 8 weeks of estrogen (conjugated equine estrogen [CEE] 0.625 mg) vs 8 weeks of placebo in the same group separated by a 4-week washout period.(97) The investigators found that estrogen produced better control, both in fasting glucose and glycated hemoglobin. The same trial also measured lipoproteins. ERT produced significant decreases in cholesterol and LDL and a significant increase in HDL. The precise mechanisms by which estrogen might improve control of diabetes need further investigation, but estrogen therapy may improve insulin resistance and may decrease the production of glucose in the liver.

Osteoarthritis

Finally, because of the effect of estrogen on bone, one study examined estrogen's impact on osteoarthritis. In the study in Figure 13, radiographs of the pelvis were obtained for 4366 women aged greater than or equal to 65 years.(98) Overall, the current use of estrogen was associated with less risk of osteoarthritis. The greatest reduction was seen in women who had used estrogen longer than 10 years.

Figure 13

Summary

The ideal scenario of health after menopause is that of maximum vigor until death. This is in contrast to the traditional concept of aging that views gradually diminishing function (fading eyesight and hearing, impaired cognitive function and memory, and decreased strength and stamina) as the norm. Although some decline is unavoidable, much of what is considered normal aging can be modified with lifestyle changes and pharmacologic interventions.

More than ever before, the menopausal woman can set a course for healthier aging. It is important for nurses to help women begin to think about menopause as a time to evaluate their health and lifestyle practices. With appropriate nurse counseling, patient information, and a thorough understanding of hormone replacement therapy, menopause can be a time for a new beginning, rather than the end of a former life. Today, women are experiencing a smooth transition into menopause due to the beneficial effects of HRT.

For nurses, helping women maximize menopausal health involves much more than understanding aging or the implications of hormone loss. It requires an ongoing effort to keep up-to-date with the options and benefits available to menopausal women. Moreover, menopause presents an important opportunity for establishing preventive health goals and helping women understand how they can be responsible for their own well-being.

Case Study 1

A 48-year-old African American woman presents for a routine examination. She is married and multiparous. She is in general good health but complains of minor changes in concentration.

Assessment

Nursing Management

Next, it is equally imperative to discuss what the patient can do to modify her disease risk. Diet, exercise, and lifestyle changes are the first issues to discuss. The patient needs to understand that these are measures she can take now to prevent chronic disease in the future. It is also important to introduce the concept of hormone replacement therapy and how it can modify her risk. Her minor concentration problems may or may not reflect the early symptoms of estrogen loss. But she should be given the information that estrogen can ameliorate the short-term symptoms of menopause as well as confer long-term benefits for osteoporosis and cardiovascular disease. And although the data are preliminary, there may be some suggestion that estrogen provides benefit in terms of diabetes and vision disorders.

The sooner and more often this discussion takes place, the better equipped patients are to make informed healthy choices that are right for them. When patients are learning complex information, it is helpful for nurses to repeat it several times and let patients absorb the message. For this reason, a discussion of menopause and HRT should begin early.

Case Study 2

This 65-year-old white woman, who is in for a routine visit, complains of insomnia, difficulty concentrating, and frequent misplacing of items. She is a retired widow who lives alone with no pets, and has limited social activities. She has never used HRT. Her daily functional ability is good.

Assessment

Nursing Management

References

1. Brinton RD, Tran J, Proffitt P, Kahil M. 17 ß -estradiol increases the growth and survival of cultured cortical neurons. Neurochemical Res. 1997;22:1339-1351.

2. Brinton RD, Proffitt P, Tran J, Luu R. Equilin, a principal component of the estrogen replacement therapy Premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. Exp Neurol. 1997;147:211-220.

3. Matsumoto A, Arai Y, Osanai M. Estrogen stimulates neuronal plasticity in the deafferented hypothalamic arcuate nucleus in aged female rats. Neurosci Res. 1985;2:412418.

4. Okhura T, Teshima Y, Isse K, et al. Estrogen increases cerebral and cerebellar blood flow in postmenopausal women. Menopause. 1995;2:13-18.

5. Simpkins JW. Presentation, Society for Neuroscience. 1995. Los Angeles.

6. Singh M, Meyer EM, Millard WJ, Simpkins JW. Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats. Brain Res. 1994;644:305-312.

7. Singh M, Meyer EM, Simpkins JW. The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger hippocampal brain expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology. 1996;136:2320-2324.

8. Sherwin BB. Impact of the changing hormonal milieu on psychological functioning. In: Lobo RE, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. New York, NY: Raven Press; 1994:119-127.

9. Phillips S, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology. 1992;17:485-495.

10. Jacobs DM, Tang M-X, Stern Y, et al. Cognitive function in nondemented older women who took estrogen after menopause. Neurology. 1998;50:368-373.

11. Rousseau ME. Women's midlife health: reframing menopause. J Nurse Midwifery. 1998;43(3):208-223.

12. Smith RNJ, Studd JWW. Estrogens and depression in women. In: Lobo RE, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. New York, NY: Raven Press; 1994:129-136.

13. Archer JSM. Relationship between estrogen, serotonin, and depression. Menopause. 1999;6:71-78.

14. Joffe H, Cohen LS, Hennen J, Carlson K. The perimenopause is a period of risk for depressive symptoms in middle-aged women [NR 13]. The American Psychiatric Association 152nd Annual Meeting, Washington DC, May 1999.

15. Stahl SM. Augmentation of antidepressants by estrogen. Psychopharmacol Bull. 1998;34:319-321.

16. Halbreich U. Role of estrogen in postmenopausal depression. Neurology. 1997;48(suppl 7):S16-S20.

17. Evans DA, Scherr PA, Cook NR, et al. Estimated prevalence of Alzheimer's disease in the United States. Milbank Mem Fund Q. 1990;68:267-289.

18. Mölsä PK, Marttila RJ, Rinne UK. Epidemiology of dementia in a Finnish population. Acta Neurol Scand. 1982;65:541-552.

19. Herbert LE, Scherr PA, Beckett LA, et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA. 1995;273:1354-1359.

20. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76:465-479.

21. Morris JC, Storandt M, McKeel DW, et al. Cerebral amyloid deposition and diffuse plaques in "Anormal" aging: evidence for presymptomatic and very mild Alzheimer's disease. Neurology. 1996;46:707-719.

22. Aronson MS, Ooi WL, Morgenstern H, et al. Women, myocardial infarction, and dementia in the very old. Neurology. 1990;40:1102-1106.

23. Brenner DE, Kukull WA, Stergachis A, van Belle G, Bowen JD, McCormick WC, Teri L, Larson EB. Postmenopausal estrogen replacement therapy on the risk of Alzheimer's disease: a population-based case-control study. Am J Epidemiol. 1994;140:262-267.

24. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer's disease. Arch Intern Med. 1996;156:2213-2217.

25. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: The Baltimore Longitudinal Study of Aging. Neurology. 1997;48:1517-1521.

26. Tang M-X, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996;348:429-432.

27. Lerner AJ, Koss E, Debanne SM, et al. Interactions of smoking history with estrogen replacement therapy as protective factors for Alzheimer's disease. Presentation, 26th Annual Meeting, Society of Neuroscience, Washington, DC. 1996.

28. Caldwell BM. An evaluation of psychological effects of sex hormone administration in aged women. J Gerontol. 1954;9:168-174.

29. Kantor HI, Michael CM, Shore H. Estrogen for older women Am J Obstet Gynecol. 1973;116:115-118.

30. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino. Low-dose estrogen replacement therapy for Alzheimer's disease in women. Menopause. 1994;1:125-130.

31. Schneider LS, Farlow MR, Henderson VW, Pogoda JM. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease. Neurology. 1996;46:1580-1584.

32. Birge SJ. The role of estrogen in the treatment of Alzheimer's disease. Neurology. 1997;48(suppl 7):S36-S41.

33. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology.1992;17:485-495.

34. Raloxifene [package insert]. Indianapolis, Ind: Eli Lilly and Company; 1998.

35. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. 1996;47:425-432.

36. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;43:1609-1611.

37. Sano M, Ernesto C, Thomas RG, et al. A controlled rial of selegiline, alpha-tocopherol or both as treatment for Alzheimer's disease. Engl J Med. 1997;336:1216-1222.

38. Speck, CE, Kukull WA. History of depression as a risk factor for Alzheimer's disease. Epidemiology. 1995;6:366-369.

39. Fitz, AG, Teri L. Depression, cognition, and functional ability in patients with Alzheimer's disease.J Am Geriatr Soc. 1994;42:186-191.

40. Schindler RJ. Behavioral problems in Alzheimer's disease: Introduction affective disorders, neurovegatative syndromes, and general principles of pharmacotherapy. Proceedings of the American Academy of Neurology 51st Annual Meeting. Toronto, Canada.1999.

41. Folstein M, Bylsma F. Noncognitive symptoms of Alzheimer's disease. In: Terry RD, Katzman R, Sisodia SS, Bick KL, ed.Alzheimer's Disease, 2nd ed. Philadelphia: Lippincott, Williams, & Wilkins; 1999;25-36.

42. Fischer P, Simanyi M, Danielczyk W. Depression in dementia of the Alzheimer's type and in multi-infarct dementia. Am J Psychiatry. 1990;147:1484-1487.

43. Donaldson C, Burns A. Burden of Alzheimer's disease; helping the patient and caregiver. J Geriatr Psychiatry Neurol. 1999;12(1):21-28.

44. Sparks MB, Farran CJ, Donner E, Keane-Hagerty E. Wives, husbands, and daughters of dementia patients: predictors of caregivers' mental and physical health. Sch Inq Nurs Pract. 1999;12:221-234; discussion 235-238.

45. Buckwalter KC, Gerdner L, Kohout F, Hall GR, Kelly A, Richards B, Sime M. A nursing intervention to decrease depression in family caregivers of persons with dementia. Arch Psychiatr Nurs. 1999:13(2):80-88.

46. Chou KR, LaMontagne LL, Hepworth JT. Burden experienced by caregivers of relatives with dementia in Taiwan. Nurs Res 1999;48(4):206-214.

47. Leblanc AJ, London AS, Aneshensel CS. The physical cost of AIDS caregiving. Soc Sci Med. 1997;45:916-923.

48. Knop DS, Bergman-Evans B, McCabe BW. In sickness and in health: an exploration of the perceived quality of the marital relationship, coping, and depression in caregivers of spouses with Alzheimer's disease. J Psychosoc Nurs Ment Health Serv. 1998;36:16-21.

49. Goode KT, Haley WE, Roth DL, Ford GR. Predicting longitudinal changes in caregiver physical and mental health: a stress process model. Health Psychol. 1998;17:190-198.

50. Yates ME, Tennstedt S, Chang BH. Contributors to and mediators of psychological well-being for informal caregivers. J Gerontol B Psychol Sci Soc Sci. 1999;54(1):P1-P22.

51. Robinson K, Austion JK. Wife caregivers' and supportive others' perceptions of the caregivers' health and social support. Res Nurs Health. 1998;21(1):51-57.

52. National Cancer Institutes. Cancer incidence in the United States (SEER), 1987-1991. Available at http://rex.nc.nih.giv/NCI_Pub_interface/raterisk/rates12.html. Accessed November 13, 1999.

53. American Cancer Society. Available at: http://www.cancer.org/statistics/cff98/selectedcancers.html. Accessed May 5, 1998.

54. Calle EE. Hormone replacement therapy and colorectal cancer: interpreting the evidence. Cancer Causes Control. 1997;8:127-129.

55. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy II: prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol. 1979;54:74-79.

56. Jacobs EJ, White E, Weiss NS. Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control. 1994;5:359-366.

57. Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst. 1995;87:517-523.

58. Sturgeon SR, Schairer C, Brinton LA, et al. Evidence of a healthy estrogen user survivor effect. Epidemiol. 1995;6:227-231.

59. Newcomb PA, Storer BE. Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst. 1995;87:1067-1071.

60. Folsom AR, Mink PJ, Sellers TA, et al. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Pub Health. 1995;85:1128-1132.

61. Troisi R, Schairer C, Chow W-H, et al. A prospective study of menopausal hormones and risk of colorectal cancer (United States). Cancer Causes and Control. 1997;8:130-138.

62. Kampman E, Porter JD, Slattery ML, et al. Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes and Control. 1997;8:146-158.

63. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128:705-712, 1998.

64. Paganini-Hill A. Estrogen replacement therapy and colorectal cancer risk in elderly women. Dis Colon Rectum. In press.

65. Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol. 1999. In press.

66. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and colorectal cancer: a review and meta-analysis. Am J Med. 1999;106:574-582.

67. Metka M, Enzelsberger H, Knogler W, Schurz B, Aichmar H. Ophthalmic complaints as a climacteric symptom. Maturitas. 1991;14:3-8.

68. The Eye-Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol. 1992;110:1701-1708.

69. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99:933-943.

70. Vingerling JR, Dielemans I, Witteman CM, Hofman A, Grobbee DE, de Jong TVM. Macular degeneration and early menopause: a case-control study. Br Med J. 1995;310:1570-1571.

71. Klein BE, Klein R, Jensen SC, Ritter LL. Are sex hormones associated with age-related maculopathy in women? The Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 1994;92:289-295.

72. Lang AE, Lozano AM. Parkinson's disease. First of two parts. Engl J Med. 1998;339:1044-1053.

73. Lang AE, Lozano AM. Parkinson's disease. Second of two parts. Engl J Med. 1998;339:1130-1143.

74. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mt Kisco, NY: Futura Publishing Company; 1989.

75. Watts RL, Koller WC, eds. Movement Disorder: Neurologic Principles and Practice. New York, NY: McGraw-Hill; 1997.

76. Rajput AH, Offord KP, Beard CM, Kurland LT. Epidemiology of parkinsonism: incidence, classification, and mortality. Ann Neurol. 1984;16:278-282.

77. Bazzett TJ, Becker JB. Sex differences in the rapid and acute effects of estrogen on striated D2 dopamine receptor binding. Brain Res. 1994;637:163-172.

78. Disshon KA, Dluzen DE. Estrogen as a neuromodulator of MPTP-induced neurotoxicity: effects upon striatal dopamine release. Brain Res. 1997;764:9-16.

79. Disshon KA, Boja JW, Dluzen DE. Inhibition of striatal dopamine transporter activity by 17beta-estradiol. Eur J Pharmacol. 1998;345:207-211.

80. Morissette M, Garcia-Segura LM, Belanger A, Di Paolo T. Changes of rat striatal neuronal membrane morphology and steroid content during the estrous cycle. Neuroscience. 1992;49:893-902.

81. McDermott JL, Liu B, Dluzen DE. Sex differences and effects of estrogen on dopamine and DOPAC release from the striatum of male and female CD-1 mice. Exp Neurol. 1994;125:306-311.

82. Blanchet PJ, Fang J, Hyland K, Arnold LA, Mouradian MM, Chase TN. Transdermal 17(ß-estradiol in postmenopausal parkinsonian patients. Mov Disord. 1998;13(suppl 2):257. Abstract.

83. Tao X, Shu-Leong H, Ramsden D. Estrogen can down-regulate the human catechol-O-methyltransferase gene expression: its implication in Parkinson's disease. Mov Disord. 1998;13(suppl 2):114. Abstract.

84. Wright CE, Sisson TL, Ichhpurani AK, Peters GR. Pramipexole and levodopa pharmacokinetics following concomitant administration. Neurology. 1997;48:185.

85. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. An examination of male-female differences in progression and mortality of Parkinson's disease. Neurology. 1990;40:763-766.

86. Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Ann Neurol. 1996;39:37-45.

87. Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders HR, Bressman S. The effect of estrogen replacement on early Parkinson's disease. Neurology. 1999;52:1417-1421.

88. Thulin PC, O'Brien SA, Filoteo JV, Roberts JW. Effect of estrogen replacement therapy on memory in women with Parkinson's disease. Mov Disord. 1998;13(suppl 2):56. Abstract.

89. Marder K, Tang M-X, Alfaro B, et al. Postmenopausal estrogen use and Parkinson's disease with and without dementia. Neurology. 1998;50:1141-1143.

90. Diabetes Facts and Figures. American Diabetes Association Web site. Available at: http://www.diabetes.org/ada/c20f.asp. Accessed January 1, 1999.

91. Eaker ED, Chesebro JH, Sacks FM, Wenger NK, Whisnant JP, Winston M. Cardiovascular disease in women. Circulation. 1993;88:1999-2009.

92. Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb. 1992;12:647-656.

93. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes and risk of coronary heart disease and stroke in women. Arch Intern Med. 1991;151:1141-1147.

94. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? JAMA. 1991;265:627-631.

95. Warram JH, Kopczynski J, Janka HU, Krolewski AS. Epidemiology of non-insulin-dependent diabetes mellitus and its macrovascular complications. Endocrinol Metab Clin North Am. 1997;26:165-188.

96. Kaplan RC, Heckbert SR, Weiss NS, et al. Postmenopausal estrogens and risk of myocardial infarction in diabetic women. Diabetes Care. 1998;21:1117-1121.

97. Friday KE, Dong C, Fontenot RU. Estrogen replacement therapy improves glycemic control and plasma lipoproteins but increases fasting triglyceride in postmenopausal type 2 diabetic women. Presented at: Annual Session of the American Diabetes Association; June 1998; Chicago.

98. Nevitt MC, Cummings SR, Lane NE, et al. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med. 1996;156:2073-2080.

Patient Handout

This might mean irritability, mood swings that don't last long, crying spells, or feelings of sadness. If you are menopausal and have recently noticed some of these symptoms, you may be experiencing an effect of estrogen loss.

How can estrogen loss change my mood?

Are these symptoms just a reflection of what's happening in my personal life?

• negative attitudes toward menopause
• poor social support
• difficulties with your marriage or family
• stressful life events
• a recent loss

How do I know if I have trouble with my memory or concentration?

Do all women experience these changes at menopause?

healthcare providers that they appear to be quite common. Remember that hormone replacement therapy can help with alterations in mood, memory, and concentration. If these symptoms are indicative of depression, then antidepressant medication may be an option as well.