Table of Contents

• Introduction
• Long-term HRT benefits
• Osteoporosis
• Cardiovascular Disease And HRT
• Safety Issues With HRT
• Case Studies
• Patient Handout

Overview

• discussing the implications of menopause and osteoporosis
• outlining the increase in cardiovascular disease risk for postmenopausal women
• describing the risk vs benefit counseling issues that can help a woman choose the therapeutic option that is appropriate for her
• providing an overview of the safety issues of HRT
• exploring the lifetime risk of developing breast cancer
• explaining the implications of an agent's safety profile

Objectives

1. describe the complications of osteoporosis
2. explain how menopause contributes to the development of osteoporosis
3. discuss how menopause contributes to cardiovascular disease
4. analyze the benefits of hormone replacement therapy in reference to osteoporosis and cardiovascular disease
5. explain the nurse's role in helping women achieve higher levels of menopausal health
6. explore the risk of developing breast cancer
7. list the contraindications for hormone replacement therapy

Introduction

Long-Term HRT Benefits

Because short- and long-term therapy have different rationales, the counseling for each may occur separately, although ideally, they would occur together. In any event, it is important to begin a discussion of long-term benefits by the time a woman is taking HRT for symptom relief.

It is also an appropriate time to begin making an assessment of a woman's risk for osteoporosis and CVD.

Osteoporosis

Osteoporosis is characterized by reductions in bone mineral density (BMD) to the extent that fractures occur after minimal trauma. It is a disease process and not a component of normal aging. Nevertheless, the incidence, patient suffering, and economic costs of osteoporosis are very significant as outlined in.(1-6)

Osteoporotic fractures (humerus, pelvic, Colles', and vertebral) in the United States total 1.5 million yearly. Although most vertebral fractures go unreported, 15% of women in their mid 60s have a vertebral fracture, and about 30% to 40% of women have such a fracture by their mid 80s.(4,5) Osteoporosis is preventable and treatable, but there are no warning signs until a fracture occurs. In essence, osteoporosis is a silent risk factor for fracture.

The most common complication of osteoporosis is hip fracture, and it is this event that is responsible for significant cost. The average cost of a hip fracture in the United States is estimated to range as high as $35,000 per patient.(3) The total annual cost reported in is derived mainly from fracture data, and does not include the cost of nursing home confinement or home healthcare.(3) Of this figure, $11 billion is attributable directly to the treatment of women.

Table 1

Aside from the cost, hip fracture is associated with significant mortality and morbidity. Roughly 20% of patients with a hip fracture die within the first month of injury.(7) In fact, most of the deaths from hip fracture occur in the first 3 to 4 months, secondary to heart failure, pulmonary embolism, or pneumonia. Death usually occurs in those who are less medically healthy at the time of fracture.

Because of the magnitude of this disease, and because there are effective therapeutic interventions, the National Osteoporosis Foundation (NOF) recently issued new recommendations for the assessment, diagnosis, and treatment of osteoporosis as listed in Table 2.(8) They provide a complete framework — from counseling to treatment.

Table 2

Osteoporosis and Menopause

The decline in a woman's BMD begins around age 18 and progresses steadily. The amount of bone present in later life is determined by the bone mass accumulated during youth and the rate of bone loss that occurs later. About 50 years ago, an association between osteoporosis and postmenopausal women was noticed. There is now little doubt that estrogen deficiency plays a very important role in the pathogenesis of bone loss. Approximately 20% of bone loss occurs in the first 5 to 7 years after menopause.(9-11)

A number of factors are associated with an increased risk for osteoporosis (Table 3). Women who are traditionally considered at greatest risk are white or Asian with a family history of osteoporosis and a small frame. More specifically, the factors that are associated with attaining maximal peak bone mass are genetic heritage, physical activity, and diet.(12,13) Factors most associated with excessive bone loss include menopause, age-related changes, declining physical activity, impaired absorption of calcium, and adverse effects of other medical conditions or drugs.(14)

White and Asian women are at highest risk of developing osteoporosis. African American and Hispanic women have a lower, but significant risk.(15) Data from the National Health and Nutrition Examination Survey (NHANES II 1998-1991) indicate that non-Hispanic white women have a prevalence that is 1.3 to 2.4 times higher than non-Hispanic black women, and 0.8 to 1.2 times higher than Mexican American women.(16) Despite these differences, it is important that African American and Hispanic women not discount their risk. African American women have higher BMD than whites throughout life, and this fact has erroneously created the impression that osteoporosis is not a concern for African American women. Recent research, however, has supported African American women as a vulnerable population, primarily because of other risk factors, not race. It is estimated that 1 in 5 African American women will be affected by osteoporosis.(17)

Table 3

Lactose intolerance may be a complicating factor in this population as well. As many as 75% of all African Americans are lactose intolerant, which is likely to interfere with the adequate intake of calcium.(18) Moreover, African American women are more likely than white women to die following a hip fracture.(18)

Both artificial and medical menopause represent areas of unrecognized importance in terms of osteoporosis risk. Some 500,000 women in the United States undergo hysterectomy and bilateral oophorectomy yearly and not all receive HRT. Bone loss in these women is likely to be significant. Six months of gonadotropin-releasing hormone (GnRH) therapy produces a 5% loss of bone at the spine, most, but not all, of which is recovered after therapy is stopped. Also, 1 year of Depo-Provera is associated with 8% bone loss, which is recovered in time with young women. Prolonged use, however, may have long-term consequences. Cigarette smoking increases the metabolism of estrogens in the liver, reducing the level of active hormone. Women who smoke are at greater risk for osteoporosis and tend to begin menopause at an earlier age.

Much of this has been confirmed in a recent study, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, which assessed the effects of HRT on bone mineral density in the spine and hip in postmenopausal women.(19) Those assigned to placebo had decreased BMD at the spine and hip, while women assigned to HRT had increased BMD during a 36-month period.

Sites of Bone Mineral Density Measurements

Reduced bone mass, irrespective of the site of measurement, is correlated with an increased risk for future fracture.(20) Thus, bone densitometry is the primary technology for diagnosing and managing patients at risk for, or with, osteoporosis (Table 4).(20,21) lists several densitometry techniques. Densitometry predicts the risk of fracture; it can be used to determine who should be treated (ie, those with low, or decreasing, bone density); and it is useful in monitoring therapeutic response.

Table 4

Such measurements can be made at central sites (spine and hip) where fractures occur. But peripheral measurements can be made as well at the hand, forearm, and heel. However, it is difficult to interpret the density at the spine from a measurement made at the forearm (radius) or heel (calcaneus).

The NOF guidelines for diagnosis and treatment are based on the World Health Organization (WHO) definition of osteoporosis, namely T-scores measured at the hip (Figure 1).(8) A T-score is obtained by comparing the patient's BMD to the expected BMD for "young normal" adults of the same sex. Although BMD measurements at any skeletal site have value in predicting fracture risk, hip BMD is the best predictor of hip fractures, and it predicts fractures at other sites.

However, WHO also uses spine T-scores. A Z-score results from a comparison to the average BMD for women of the patient's age.

Figure 1

ERT/HRT for Osteoporosis

Figure 2

The most recent results from the PEPI trial (3-year longitudinal study) show significant benefits of estrogen therapy (0.625 mg of conjugated equine estrogen or CEE) in terms of maintenance of bone density at the spine.(19) The PEPI population was age 52 on average. Figure 2 presents only those patients who were adherent to the prescribed regimen. Consistent therapy can produce about a 5% increase in spine density. Also, continuous progesterone (medroxyprogesterone acetate or MPA) therapy resulted in significantly higher BMD compared to cyclic progesterone therapy. Similar results were seen at the femoral neck, where consistent adherence produced about a 2% increase in BMD.

Estrogen therapy should be initiated as soon as possible after menopause or ovarian failure because lost bone mass may never be recovered. A placebo-controlled study of 16 years' duration dramatically showed the effects of estrogen deficiency on bone loss in oophorectomized women.(22) Several results of the study were noteworthy. Metacarpal mineral content decreased 20% over 15 years in women who did not take estrogen. Estrogen therapy retarded bone loss irrespective of whether the treatment was started at 0, 3, or 6 years after oophorectomy. And lost bone mass was not replaced. Thus, the earlier estrogen replacement therapy is started after menopause, the more protective its effect on bone density. Moreover, it is never too late to start HRT and gain improvement. It is important to note that the effective dose of estrogen varies according to the type of estrogen compound (Table 6).

Table 6

In addition to having a role in the prevention of osteoporosis, estrogen is beneficial in treatment. A number of studies have examined the ability of HRT to reduce the incidence of fractures. Because the highest incidence of radial and vertebral fractures occurs mainly between 50 and 75 years of age, the effect of estrogen on these fracture rates is easier to detect than its effect on hip fractures, which start in the late 70s. Relative risk (RR) is defined in Table 7. The relative risk graph in Figure 3 shows several case-control and cohort studies that have compared estrogen use in hip fracture cases with estrogen use in controls. These studies showed reductions in fracture risk of 20% to 60%.(23)

Figure 3

Table 7

Therapeutic Alternatives for Osteoporosis

Figure 4 shows a prevention trial that involved a direct comparison of placebo, alendronate, and HRT.(28)

The women who received placebo lost BMD, whereas those treated with alendronate had a mean increase of 3.5% at the spine, and 1.9% at the hip. The responses to HRT were 1% to 2% greater than responses to alendronate. Another prospective study involved about 2,000 women who were randomized to either placebo or alendronate.(29) Significantly fewer women in the alendronate group had vertebral fractures (RR 0.45 [0.27-0.72]). The RR of hip fractures among the treated group was 0.49 (0.23-0.99).

Figure 4

The newest SERM, raloxifene, is also approved to treat osteoporosis. It produces an increase in BMD of about 1% at the hip,30,31 which is lower than the increase seen with estrogen. Although there is a 2% difference between raloxifene and placebo, this SERM is not as effective as estrogen on bone density.

Calcitonin is another therapeutic alternative that slows bone density loss, but it is not as effective as the other agents previously mentioned. There are 2 major US studies that show the effect of calcitonin in postmenopausal women. One showed that in the early menopause, that is, within 4 years, calcitonin was no better than placebo in preventing bone loss.(32) The other study suggests that in late menopause (>10 years since menopause) there is some evidence that calcitonin prevents bone loss.(33) Therapy with this agent produced increases in BMD of 1% to 2%.

The evidence available for elemental calcium supplementation shows only a very modest beneficial effect on osteoporosis. However, habitual dietary intake influences the efficacy of supplementation. Women with low intake to begin with benefit the most. In early menopause calcium supplementaion is ineffective,34 but in late menopause it reduces bone loss by 25% to 30%.(35,36) RDA nutritional requirements and recommendations from the NIH consensus statement suggest 800 mg of elemental calcium premenopause

and 1500 mg postmenopause. The NOF recommends 800 mg before menopause and 1200 mg after. Among the current options for treating osteoporosis, CEE and alendronate are the most potent, but not all treatment options have equal preventive and treatment efficacy. Although bone density may be increased or maintained by several therapies, not all treatments have been shown to reduce fracture rates (Table 8). Fluoride treatment shows the largest increase in BMD, yet the effect on fracture rates is unproven, perhaps because of changes in the quality of bone. Thus, increases in BMD do not always equate with fracture prevention efficacy.

Table 8

Effect Of HRT On Tooth Loss

In addition to ameliorating osteoporosis, estrogen may provide benefit for another condition that involves the skeletal system, that is, tooth loss. Approximately 32% of US women aged 65 have no teeth. Although the prevention of periodontal disease is the most important factor in maintaining teeth, it has been hypothesized that some tooth loss may occur as a result of resorption of the alveolar bone and therefore reflects osteoporotic bone loss. There is some evidence that bone mineral density in postmenopausal women is correlated with the number of teeth.(37-39) The 3 studies in the RR risk graph in Figure 5 show that estrogen therapy is associated with a decreased risk of tooth loss in both past users and current users.(40-42)

Figure 5

Comprehensive Approach To Osteoporosis

Cardiovascular Disease and HRT

The Impact of CVD After Menopause

Statistics show overwhelmingly that CVD – and not cancer – is the leading cause of mortality for postmenopausal women (Figure 6).(43) In fact, 1 in 2 women will eventually die of heart disease or stroke, compared to 1 in 25 women who will die because of breast cancer.(44) The incidence of heart disease, including coronary artery disease and stroke, is rare in premenopausal women.

Figure 6

However, heart disease is the most frequent cause of death in women over the age of 50.(45,46) Despite the impact of CVD, only 35% of women in a recent survey related heart disease to menopause.(47) Although there has been a gradual and pronounced decrease in cardiovascular deaths in this country, thedecrease has not occurred equally among men and women. Since 1984, death rates for men have dropped, while cardiovascular death rates for women have increased (Figure 7).(43) It is possible that estrogen replacement at menopause could have an impact on these mortality curves. Currently, however, only 16% of women receive HRT after natural menopause, and 50% of these stop therapy within a year. Thus, treatment must become widespread before it might have a visible impact on mortality trends.

Figure 7

The Cardioprotective Effects of Estrogen

The fact that estrogen loss and aging are associated with a dramatic increase in cardiovascular disease among women has focused research on the cardioprotective effects of estrogen.(48) The data presented in the RR scale in Figure 8 are based on retrospective observational studies.(49-59) Most of these observational studies show a reduction in relative risk for CVD, and a meta-analysis of these data indicate a risk ratio of 0.5 (a 50% reduction in risk). However, the first, and only, placebo-controlled, retrospective study is the ongoing Women's Health Initiative.

Figure 8

Other studies have examined whether estrogen would confer a protective effect on women with established coronary artery disease (CAD). Several secondary prevention studies show that estrogen use in these women reduces the risk of death and future events by 50% to 90% (Table 9).(56,60-64) This degree of reduction in risk is marked, and is comparable to that observed following successful treatment of LDL cholesterol elevations.

Table 9

The results from the most recent of these studies, the Heart and Estrogen/ Progestin Replacement Study (HERS) trial, are not consistent with the previous studies.(64) In the HERS trial, HRT was evaluated over 4 years in women with established CHD as a treatment for preventing CHD progression, specifically nonfatal myocardial infarction (MI) and death from CHD.

The article reported that in the first year of the study, women treated with HRT experienced an increase in second CHD events compared with placebo (RR 1.52, 1.01-2.29). With continuing treatment, however, this initial increase was reversed, and HRT resulted in a reduction in second CHD events by the fourth and fifth years of treatment (RR 0.67, 0.43-1.04). What does this mean in terms of counseling women about HRT? The HERS study was not designed to evaluate primary prevention in a population of healthy women, who represent the most typical users of HRT. Rather, it looked at a subset of women with an average age of 67 years who have established CHD. Thus, this study should have no impact on the routine use of HRT for cardiovascular benefits in healthy women.

For postmenopausal women with established heart disease, there is no reason to stop their HRT if they have no problems. Those women with established disease who are not currently on HRT need to make individual decisions about the risk/benefit ratio.

Mechanisms of Estrogen's Cardiovascular Effects

Plaque (the basic coronary lesion) development has 2 components, lipid and nonlipid, and estrogen exerts a cardioprotective effect via both of these mechanisms (Figure 9).(65-67) Estrogen reverses the adverse changes in lipid metabolism associated with menopause.(15,68) Roughly a quarter of estrogen's effect is related to this action. But estrogen also exerts a second, lipid-independent effect by directly modifying the function of the endothelium and vascular smooth muscle. These endothelial effects account for the majority of estrogen's cardioprotection.

Figure 9

The PEPI trial confirmed the lipid benefits of HRT.(69) Estrogen, taken alone or in combination with progestin, improves a woman's lipid profile (increases HDL and decreases LDL) and lowers fibrinogen levels (Figure 10).(15,69) In general, the addition of progestin to estrogen slightly reduces, but does not eliminate, the lipid benefits of estrogen alone. Fasting insulin levels decreased slightly, but not significantly, in women taking estrogen, and fasting glucose decreased significantly in all treatment arms compared with placebo.

Estrogen also acts through a second mechanism, directly on the endothelium. The ability of arteries to dilate when they should, rather than to constrict, is one of their most important properties. This function is modulated by the endothelium. If the endothelium is functioning normally, acetylcholine challenge results in dilation of the coronary arteries. But if there is vascular dysfunction, acetylcholine results in constriction. In a classic study, acetylcholine challenge in normal arteries caused a dilation that was associated with increased blood flow.(70) But when diseased arteries were challenged, it resulted in constriction of the arteries and reduced flow. Treatment with estrogen restored their ability to dilate and, thus, to increase blood flow.

Figure10

Options for Cardioprotection

Drug therapy for hypercholesterolemia, particularly for women, has remained controversial mainly because of insufficient clinical evidence that treatment enhances survival. Two recent reports, however, prove there are significant treatment benefits. The Scandinavian Simvastatin Study showed similar benefits for men and women.(73) Both experienced about a 35% decrease in risk for major coronary events when treated with statins (21.7% placebo vs 14.5% simvastatin for women and 29.4% placebo vs 20.5% simvastatin for men). Statin therapy also improved survival in a second study, the Air Force Texas study presented at the American Heart Association.(74) In this study, women had a greater percent reduction in first cardiac events than men (54% for women and 34% for men, P = 0.001.

Antioxidant vitamins are commonly taken by postmenopausal women with the expectation that they may provide some cardioprotection. Whether, and to what extent, they do so is largely based on observational data (Table 10).(75)

Observational studies have suggested that increased intake of vitamins A, C, and E; beta-carotene; flavonoids; and folic acid, by diet or supplement, reduces cardiovascular event rates. For example, Stampfer et al reported a protective effect on the risk of coronary heart disease with vitamin E consumption in the Nurses' Health Study.(76) When subjected to randomized controlled trials, only vitamin E, in doses of 400 to 800 IU daily, significantly reduced the rate of recurrent myocardial infarction. It seems doubtful, however, that a similar beneficial effect is shared by beta-carotene.(77) Folic acid appears to be beneficial, but not as an antioxidant. Its beneficial effect on cardioprotection is by way of lowering plasma concentrations of homocysteine. Aspirin is another option for CVD prevention in postmenopausal women. In a study of high-risk patients, prolonged aspirin treatment (of 1 month or more) offered significant protection against myocardial infarction, stroke, and death. Such therapy reduced vascular events by about 25%. This benefit was seen in those over 65 years of age and was equal in men and women.(78)

Table 10

The SERM raloxifene is being recommended for some postmenopausal women rather than traditional hormone replacement therapy.(31) Because coronary heart disease is the leading cause of death among post-menopausal women, it is important to know how raloxifene compares with traditional therapy in terms of affecting the lipid/lipoprotein profile. Figure 11 shows a comparison of the effects of raloxifene and CEE on the plasma lipid profiles of postmenopausal women.(31,79) Raloxifene is somewhat less effective than CEE in reducing plasma LDL concentrations, and whereas CEE has markedly beneficial effects on increasing HDL concentrations, no such benefit is observed with raloxifene treatment. CEE results in modest increases in plasma triglycerides, which are not seen with raloxifene treatment. However, no adverse effects on coronary heart disease inhibition have been shown because of these modest increases in plasma triglyceride concentrations.

Figure 11

In summary, the postmenopausal woman has a number of therapeutic options, including HRT, for offsetting the cardiovascular effects of estrogen deprivation. (Other long-term benefits of HRT will be discussed in Monograph 3.)

Safety Issues with HRT

• known or suspected pregnancy
• known or suspected breast cancer
• estrogen-dependent neoplasia
• undiagnosed abnormal genital bleeding
• active thromboembolic disorders

Ongoing research, however, suggests that some of these contraindications may not be absolute. In the meantime, all the relative contraindications must be carefully discussed with patients and weighed against the risk of not prescribing HRT, especially for women with CVD. If HRT is inappropriate, other options should be considered that are specific for each patient's risk of disease.

This is also a good time to discuss the common concerns that women have about HRT. The multiple benefits of long-term postmenopausal hormone therapy represent an attractive preventive healthcare option for most women. But safety concerns may cause many women to discontinue, or not initiate, therapy. The most common of these issues is fear of breast cancer. Helping patients understand the true risk of breast cancer, and the true contribution of HRT, is critical.

Figure 12

Women have a lifetime risk of developing breast cancer of about 1 in 8.(46) The risk of developing breast cancer increases with a woman's age. But it is also related to her decade in life. For example, a woman who is 40 years of age has a 10% risk of developing breast cancer by the time she reaches 80. A woman who is 70, however, has only a 4% risk of developing breast cancer by the time she reaches 80.(81)

White non-Hispanic women have the highest incidence rate for breast cancer among racial and ethnic groups in the United States (Figure 12).(82) But African American women have the highest mortality rate for breast cancer. Although there has been an increase in the overall incidence of breast cancer among all women, mortality rates have not increased (Figure 13).(83) Part of the explanation for this is that breast cancer is being diagnosed earlier (carcinoma in situ), at a time when treatment is more likely to be effective.(84, 85)

Figure 13

Mammography for Early Detection

• National Cancer Institute (NCI)
• Every 1 to 2 years for women in their 40s
• Every 1 to 2 years for women aged 50 and over
• Women who are at higher than average risk of breast cancer should seek medical expert advice about the frequency of screening and whether they should begin screening before age 40.
• American Cancer Society (ACS)
• Every year beginning at age 40
• American College of Obstetricians and Gynecologists (ACOG)
• Every 1 to 2 years for women in their 40s
• Every year for women aged 50 and older According to the NCI, early detection messages may be particularly important for several minority groups that include:
• African American women – they have the highest mortality and lowest survival rates for breast cancer
• Hispanic women – breast cancer incidence rates are increasing faster among Hispanics than other women
• American Indian or Alaska Native women – they have higher breast cancer incidence rates and lower survival rates than some other groups of women.
• Asian or Pacific Islander women – some studies suggest that their cancer rates increase as they become acculturated

Breast Cancer Studies

Over 50 studies have examined the relationship between ERT/HRT and breast cancer. The RR scale in Figure 14 shows there is no clear trend in regard to such an association.(90-100) Nursing literature draws a similar conclusion.(15,68) One 10-year, prospective double-blind study that investigated breast cancer and estrogens found no increase in breast cancer risk with estrogen therapy.(101) None (0/84) of the estrogen-treated women (2.5 mg of conjugated equine estrogen po qd and MPA 10 mg po qd for 7 days per month) developed breast cancer compared to 4.7% (4/84) of those who did not receive HRT (P <.061). The study suggested that the addition of progestin to HRT did not seem to increase breast cancer risk.

Figure 14

At the end of the 10-year study, a follow-up study began. Patients were given the option of continuing, discontinuing, or starting estrogen therapy. Those who chose estrogen took 0.625 mg po qd and MPA 10 mg po qd for 10 days per month. This follow-up lasted another 12 years, resulting in a 22-year study with 3271 patient years. It showed that patients treated with estrogen had no increased risk of developing breast cancer.(102) None of those receiving HRT (0/116) developed cancer, while 11.5% never users (6/52) did develop breast cancer (P <.001). Even among several meta-analyses, there does not appear to be an increase in breast cancer risk in women taking estrogen replacement therapy.(91,103-107) Several points arising from the studies were noteworthy. Looking at all women who had ever used estrogen, either currently or in the past, showed that ERT had no effect on breast cancer risk.

A number of these studies altered the analysis to examine the effect of duration of estrogen use. Increasing duration produced a slight increase in RR of breast cancer that was inconclusive. Also, there was no consistent association of ERT and breast cancer risk in patients with a family history of benign breast disease.

A recent reanalysis of epidemiological data on more than 160,000 women from 51 investigation centers showed an increase in risk of breast cancer with HRT.(108) Ever use (both current and former use combined) had a RR of 1.14, current HRT use had a RR of 1.35, and former use was associated with a RR of 1.07. The RRs for ever and current use were based on a factor of 2.3% increase/year of use and were statistically significant. The size of the study is noteworthy (the conclusions are based on 17,949 cases of breast cancer), but a closer look may be warranted given the unexpected nature of its findings.

There was a lack of agreement and uniformity among the centers. In addition, the study produced inconsistent results about duration: the group using hormones for 10 to 14 years had no statistical evidence of an increase in risk (RR 1.09). The RR was decreased for former users, which is inconsistent biologically. Moreover, the conclusion that current and recent users had evidence of only localized disease suggests bias. Less aggressive tumors and better survival rates in hormone users may suggest earlier detection. Despite the discrepancies among numerous studies, there is no clear, compelling evidence for an association between estrogen replacement therapy and breast cancer. In general, women must be given information about what current studies indicate and the fact that there is no clear trend.

Then, it is the responsibility of healthcare professionals to help them make a decision about HRT that is comfortable for them.

Family History

There is little or no evidence to support the common perception that a family history of breast cancer contraindicates HRT. A recent study (Table 11) found that there was no significant increase in breast cancer with hormone use among women with a such a family history.(109) There was, however, a significant reduction in total mortality. Such a benefit in overall mortality has also been found among women who use ERT/HRT in general.

Table 11

The study detailed in Figure 15 found that mortality from any cause among women postmenopausal women who used ERT/HRT was lower than among nonusers.(110) The survival benefits were most apparent for current users (RR 0.63, CI = 0.56-0.70), and were greatest for coronary heart disease (RR 0.47, CI = 0.32-0.69). The protective effect of hormones persists for 3 to 4 years after therapy is stopped but is lost after 5 years. Among short-term users of therapy, there was a significant reduction in breast cancer risk (past RR 0.83, CI = 0.63-1.09 and current RR 0.76, CI = 0.56-1.02). Moreover, in a subgroup of women with a family history of breast cancer, the RR was 0.65, CI = 0.47-0.90.

Figure 15

HRT and Women Who Develop Breast Cancer

In one of these studies that involved 6000 women, the relative survival rate was significantly higher (P = 0.02) by about 10 percentage points at 8 years in women who had received HRT.(111) This higher survival advantage was found only in women over the age of 50 and was most pronounced in recent HRT users, that is, patients who had discontinued hormone therapy less than 1 year prior to diagnosis.

Although the use of HRT in women who have a history of breast cancer is controversial, there is also evidence that these women may benefit from such treatment after diagnosis in terms of recurrences and death.(115-119)

Summary Of Breast Cancer Issues

the diagnosis of breast cancer, and hormone therapy may improve the patient's quality of life. A survey among women with breast cancer suggests that these women are very aware of and concerned about the adverse health consequences of estrogen deficiency and would consider ERT under medical supervision.(120)

Other Safety Issues

It has been demonstrated in a number of studies that the addition of progestins to ERT clearly reduces the risk of endometrial cancer to that of never-users.(124,125) The most current of the studies that demonstrates this found a RR of 5 (1.6-5.9) for women who took estrogen only (Table 12).(124) However, the relative risk of endometrial cancer was only 0.9 (0.7-1.2) among those who received estrogen and progestin.

Table 12

Another safety issue that has received attention with HRT use is stroke. The majority of studies have found that estrogen therapy has no effect on risk of stroke (Figure 16). Wilson et al, the Framingham Study, reported an increased risk of stroke among postmenopausal hormone users, but confidence intervals were not calculated.(126) Four of these 5 studies found that HRT lowered the risk of stroke in postmenopausal women.(127-130)

Figure 16

There has also been some concern about primary pulmonary embolism (PE) with estrogen. A classic study found an increased risk of PE with current HRT use among postmenopausal women.(131) The risk is diminished, however, with past HRT use. Primary PE was uncommon in this population of healthy women.

One final safety issue with estrogen that has received some attention is deep venous thromboembolism (DVT). Two studies found an increased risk of DVT among current hormone users.(132,133) However, one of these studies reported that the increased risk may be concentrated in new users, and the other suggested that the absolute risk was low and accounted for only a modest risk in mortality. A third study found no increased risk with HRT at all.(134) Raloxifene carries the same risk for DVT as estrogen.

Estrogen, as part of HRT, is a comprehensive therapy that offers benefit to the majority of menopausal women. When risks and benefits are weighed, it is appropriate therapy that offers

both short-term and long-term benefits. For the perimenopausal women, HRT counseling must go beyond symptom control to include prevention of heart disease and osteoporosis. Control of body weight and of alcohol and tobacco consumption, encouragement of regular exercise, maintenance of mental health including sexuality, and cancer screening are other counseling issues. Nurses are in a unique position to help women make the choice that is right for them.

Case Study 1

Perimenopause

On a routine office visit, this 51-year-old African American woman complains of hot flushes, sleep disruption, and irritability. She has been amenorrheic for 12 months. Although she knows about hormone replacement therapy, she says that she can't take estrogen because her sister had breast cancer.

Assessment

She has a family history of heart disease (mother died of MI at 65 years) and breast cancer (sister at 60 years). The patient is 5'3", and weighs 160 lbs. A lipid profile reveals high cholesterol: total cholesterol 267 mg/dL, HDL 42 mg/dL, LDL 160 mg/dL, and triglycerides 250 mg/dL.

Nursing Management

Accurate counseling about the risks and benefits of HRT is important so that this patient can make an informed choice about her health. A family history of breast cancer is not a contraindication for HRT, and this patient could benefit from the cardioprotection offered by estrogen.

Case Study 2

Menopause and Osteoporosis

This 48-year-old white woman is in the office for an annual exam. Her height is 5'7" and she weighs 130 lbs. The patient has a sedentary lifestyle, smokes 1 pack of cigarettes per day, and is menopausal.

Assessment

In addition to the standard care for a woman this age (GYN exam and mammography) a dual-energy x-ray absorptiometry (DXA) test for BMD is ordered. During a discussion about osteoporosis and HRT, the patient decides that she does not want to initiate this therapy. She dislikes dairy products and does not take any vitamin or mineral supplements.

Nursing Implications

This patient has several risk factors for osteoporosis. Because the DXA results are pending, a return office visit provides another opportunity to discuss her risk for osteoporosis.

References

1. National Osteoporosis Foundation. Available at: http://www.nof.org/other/statistics.html. Accessed April 6, 1998.

2. Melton LJ III, Thamer M, Ray NF, et al. Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:16-23.

3. Ray NF, Chan JK, Thamer M, Melton LJ III. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:24-35.

4. Cooper C, Melton LJ III. Epidemiology of osteoporosis. Trends Endocrinol Metab. 1992;3:224-229.

5. Cooper C, Campion G, Melton LJ III. Hip fracture in the elderly: a world-wide projection. Osteoporosis Int. 1992;2:285-289.

6. Cooper C, Atkinson EJ, O'Fallon WM, Melton LJ III. The incidence of clinically diagnosed vertebral fractures; a population-based study in Rochester, Minnesota, 1985-89. J Bone Miner Res. 1992;7:221-227.

7. Gallagher JC, Melton LJ, Riggs BL, Bergstrath E. Epidemiology of fractures of the proximal femur in Rochester, Minnesota. Clin Orthop Relat Res. 1980;150:163-171.

8. Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 1998.

9. DeFazio J, Speroff L. Estrogen replacement therapy: Current thinking and practice. Geriatrics. 1985;40(11):32-48.

10. Peck WA, Riggs BL, Bell NH. Physician's Resource Manual on Osteoporosis. Washington, DC: National Osteoporosis Foundation; 1987.

11. Mahon S. Osteoporosis: a concern for cancer survivors. Oncol Nurs Forum. 1998;25:843-853.

12. Burckhardt P, Michael C. The peak bone mass concept. Clin Rheumatol. 1989;8(suppl 2):16-21.

13. Sowers MR, Galuska DA. Epidemiology of bone mass in premenopausal women. Epidemiol Rev. 1993;15:374-398.

14. Riggs BL, Melton LJ III. Medical progress: involutional osteoporosis. Engl J Med. 1986;314:1676-1686.

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

16. Looker AC, Wahner HW, Dunn WL, et al. Updated data on proximal femur bone mineral levels of US adults. Osteoporosis Int. 1998:8:468-489.

17. Huff M, Sadler C. African American women and osteoporosis. ABNF J. 1997;May/June:48-50.

18. National Institutes of Health Osteoporosis and Related Bone Diseases~National Resource Center. Available at: http://www.osteo.org/r607afrc.htm. Accessed May 26, 1999.

19. The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. JAMA. 1996;276:1389-1396.

20. Cummings SR, Black DM, Nevitt MC, et al and the Study of Osteoporotic Fractures Research Group. Appendicular bone density and age predict hip fracture in women. JAMA. 1990;263:665-668.

21. Notelovitz M. Osteoporosis: screening, prevention, and management. Fertil Steril. 1993;59:707-725.

22. Lindsay R. The menopause: sex steroids and osteoporosis. Clin Obstet Gynecol. 1987;30:847-859.

23. Gallagher JC. Estrogen: Prevention and treatment of osteoporosis. In: Marcus, et al, eds. Osteoporosis. San Diego, Calif: Academic Press; 1996:chap 63.

24. Ott SM. Clinical effects of bisphosphonates in involutional osteoporosis. J Bone Miner Res. 1993;8(suppl 2):S597-S606.

25. Pacifici R, McMurtry C, Vered I, Rupich R, Avioli LV. Coherence therapy does not prevent axial bone loss in osteoporotic women: a preventive comparative study. J Clin Endocrinol Metab. 1988;66:747-753.

26. Chesnut CH, McClung MR, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995;99:144-152.

27. Rossini M, Gatti D, Zamberlan , Braga V, Dorizzi R, Adams S. Long-term effects of a treatment course with oral alendronate on postmenopausal osteoporosis. J Bone Miner Res. 1994;9:1833-1837.

28. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Engl J Med. 1998;338:485-492.

29. Black DM, Cummings SR, Karpf DB, for the Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.

30. Delmas PD, Bjanrson NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. Engl J Med. 1997;337:1641-1647.

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

32. Campodarve I, Drinkwater BL, Insogna KL, et al. Intranasal salmon calcitonin (INSC), 50-200 IU, does not prevent bone loss in early postmenopausal women [abstract]. J Bone Miner Res. 1994:9(suppl 1):S391.

33. Overgaard K, Riis BJ, Christiansen C, Podenphant J, Johansen JS. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol (Oxf). 1989;30:435-442.

34. Aloia JF, Vaswani A, Yeh JK, Ross PL, Flaster E, Dilmanian FA. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med. 1994;120:97-103.

35. Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med. 1995;98:331-335.

36. Dawson-Hughes B, Dallal GE, Krall EA, Sadowski L, Sahyoun, Tannenbaum S. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. Engl J Med. 1990;323:878-883.

37. Jeffcoat MK, Chesnut CH. Systemic osteoporosis and oral bone loss. J Am Dent Assoc. 1993;124(November):49-56.

38. Kribbs PJ, Chesnut CH, Ott SM, Kilcoyne RF. Relationships between mandibular and skeletal bone in a population of normal women. J Prosthet Dent. 1990;63:86-89.

39. Daniell HW. Postmenopausal tooth loss. Contributions to edentulism by osteoporosis and cigarette smoking. Arch Intern Med. 1983;143:1678-1682.

40. Grodstein F, Colditz GA, Stampfer MJ. Post-menopausal hormone use and tooth loss: a prospective study. J Am Dent Assoc. 1996;127:370-377.

41. Paganini-Hill A. The benefits of estrogen replacement therapy on oral health. Arch Intern Med. 1995;155:2325-2329.

42. Krall EA, Dawson-Hughes B, Hannan MT, Wilson PW, Kiel D. Postmenopausal estrogen replacement and tooth retention. Am J Med. 1997;102:536-542.

43. 1999 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1999.

44. 1997 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1997.

45. National Center for Health Statistics. Vital Statistics of the United States. 1992, Vol II B Mortality, Part A. Hyattsville, Md: US Dept of Health and Human Services, Public Health Service; 1996. DHHS publication 96-1101.

46. Miller et al, eds. SEER Cancer Statistics Review, 1973-1993. Bethesda, Md: National Cancer Institute; 1997.

47. Wyeth-Ayerst Fourth Annual Menopause Report. 1996.

48. Millonig VL. Menopause: health promotion opportunities for the occupational health nurse. AAOHN Journal. 1996;44:585-597.

49. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. Engl J Med. 1985;313:1044-1049.

50. Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation. 1987;75:1102-1109.

51. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: Long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol. 1987;70:289-293.

52. Boysen G, Nyboe J, Appleyard M, Sorensen PS, Boas J, Somnier F. Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke. 1988;19:1345-1353.

53. Criqui MH, Suwarez L, Barrett-Connor E, McPhillips J, Wingard DL, Garland C. Postmenopausal estrogen use and mortality. Am J Epidemiol. 1988;128:606-614.

54. Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol. 1988;159:312-317.

55. van der Giezen AM, Schopman-Geurts van Kessel JG, Schouten EG, Slotboom BJ, Kok FJ, Collete HJ. Systolic blood pressure and cardiovascular mortality among 13,740 Dutch women. Prev Med. 1990;19:456-465.

56. Wolf PH, Madans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. Am J Obstet Gynecol. 1991;164:489-494.

57. Falkeborn M, Persson I, Adami HO, Bergstrom R, Eaker E, Lithell H. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol. 1992;99:821-828.

58. Psaty BM, Heckbert SR, Atkins D, Lemaitre R, Koepsell TD, Wahl PW. The risk of myocardial infarction associated with the progestins in postmenopausal women. Arch Intern Med. 1994;154:1333-1339.

59. Folsom AR, Mink PJ, Sellers TA, Hong CP, Zheng W, Potter JD. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health. 1995;85:1128-1132.

60. Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med. 1990;150:2557-2562.

61. Bush TL. Long term effect of estrogen use on cardiovascular death in women. Presented at: American Heart Association; 1991; Orlando.

62. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75-78.

63. Newton KM, LaCroix AZ, McKnight B, Knopp RH, Siscovick DS, Heckbert SR, Weiss NS. Estrogen replacement therapy and prognosis after first myocardial infarction. Am J Epidemiol. 1997;145:269-277.

64. Hulley S, Grady D, Bush T, et al for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.

65. Gerhard M, Ganz P. How do we explain the clinical benefits of estrogen? From bed side to bench. Circulation. 1995;92:5-8.

66. Sullivan JM. Hormone replacement therapy in cardiovascular disease: The human model. Br J Obstet Gynaecol. 1996;103(suppl 13):50-67.

67. Clarkson TB, Anthony MS. Effects on the cardiovascular system: basic aspects. In: Lindsay R, Dempster DW, Jordan VC, eds. Estrogens and Antiestrogens. Philadelphia, Pa: Lippincott-Raven Publishers; 1997:89-118.

68. Keller C, Fullerton J, Fleury J. Primary and secondary prevention strategies among older postmenopausal women. J Nurse Midwifery. 1998;43:262-272.

69. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-208.

70. Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA, Gerstenblith G, Brinker JA. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation. 1994;89:52-60.

71. Darling GM, Johns JA, McCloud PI, Davis SR. Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. Engl J Med. 1997;337:595-601.

72. Davidson MH, Testolin LM, Maki KC, von Duvillard S, Drennan KB. A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women. Arch Intern Med. 1997;157:1186-1192.

73. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

74. Gotto et al. Presented at: American Heart Association; 1997; Orlando.

75. Jha P, Flather M, Lonn E, Farkouh M, Yusuf S. The antioxidant vitamins and cardiovascular disease. Ann Intern Med. 1995;123:860-872.

76. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. Engl J Med. 1993;328:1444-1449.

77. Nenseter MS, Volden V, Berg T, Drevon CA, Ose L, Tonstad S. No effect of b-carotene supplementation on the susceptibility of low density lipoprotein to in vitro oxidation among hypercholesterolaemic, postmenopausal women. Scan J Clin Lab Invest. 1995;55:477-485.

78. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy — I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J. 1994;308:81-106.

79. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;279:1445-1451.

80. Premarin [package insert]. Philadelphia, Penn: Wyeth-Ayerst Laboratories; 1998.

81. Feuer EJ, Wun L-M, Boring CC, Flanders WD, Timmel MJ, Tong T. The lifetime risk of developing breast cancer. J Natl Cancer Inst. 1993;85:892-897.

82. National Cancer Institute. Cancer Facts. Available at: http://198.77.70.126_29.htm. Accessed May 25, 1999.

83. Ries LAG. Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK, eds. SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute; 1999.

84. Miller BA, Feuer EJ, Hakney BF. Eng J Med. 1992;327:1756-1757. Letter.

85. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. Engl J Med. 1992;327:319-328.

86. Huey FL. NIH consensus statement on breast cancer screening for women in the 40s: how will it affect patient care? Medscape Women's Health. 1997;2(4). Available at: http://www.medscape.com.

87. American College of Obstetricians and Gynecologists. Available at: http://www.acog.com/from_home/publications/press_releases/nr-mammos.htm. Accessed May 25, 1999.

88. American Cancer Society. Available at: http://www. cancer.org/media/story/1mar23.htm. Accessed May 25, 1999.

89. National Cancer Institute. Available at: http://rex.nci.gov/massmedia/pressreleases/ncabrecommend_part3.html. Accessed May 25, 1999.

90. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. Engl J Med. 1995;332:1589-1593.

91. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

92. Kaufman DW, Palmer JR, de Mouzon J, et al. Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study. Am J Epidemiol. 1991;134:1375-1385.

93. Palmer JR, Rosenberg L, Clarke EA, Miller DR, Shapiro S. Breast cancer risk after estrogen replacement therapy: results from the Toronto Breast Cancer Study. Am J Epidemiol. 1991;134:1386-1395.

94. Risch HA, Howe GR. Menopausal hormone usage and breast cancer in Saskatchewan: a record linkage cohort study. Am J Epidemiol. 1994;139:670-683.

95. Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes Control. 1994;5:491-500.

96. La Vecchia C, Negri E, Franceschi S, et al. Hormone replacement therapy and breast cancer risk: a cooperative Italian study. Br J Cancer. 1995:72;244-248.

97. Schuurman AG, van den Brandt PA, Goldbohm RA. Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control. 1995;6:416-424.

98. Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA. 1995;274:137-142.

99. Newcomb PA, Longnecker MP, Storer BE, et al. Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol. 1995;142:788-795.

100. Vassilopoulou-Sellin R. Estrogen replacement therapy in women at increased risk for breast cancer. Breast Cancer Res Treat. 1993;28:167-177.

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

102. Nachtigall MJ, Smilen SW, Nachtigall RD, Nachtigall RH, Nachtigall LE. Incidence of breast cancer in a 22-year study of women receiving estrogen-progestin replacement therapy. Obstet Gynecol. 1992;80:827-830.

103. Armstrong BK. Oestrogen therapy after the menopause — boon or bane? Med J Aust. 1988;148:213-214.

104. Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders D, Berkelman RL. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 1991;265:1985-1990.

105. Sillero-Arenas M, Delgado-Rodriguez M, Rodigues-Canteras R, Bueno-Cavanillas A, Galvez-Vargas R. Menopausal hormone replacement therapy and breast cancer: a meta-analysis. Obstet Gynecol. 1992;79:286-294.

106. Colditz GA, Egan KM, Stampfer MJ. Hormone replacement therapy and risk of breast cancer: Results from epidemiologic studies. Am J Obstet Gynecol. 1993;168:1473-1480.

107. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-1037.

108. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet. 1997;350:1047-1059.

109. Sellers TA, Mink PJ, Cerhan JR, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med. 1997;127:973-980.

110. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. Engl J Med. 1997;336:1769-1775.

111. Bergkvist L, Adami H-O, Persson I, Bergstršm R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol. 1989;130:221-228.

112. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol. 1990;97:1080-1086.

113. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75-78.

114. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control. 1996;7:449-457.

115. Stoll BA. Hormone replacement therapy for women with a past history of breast cancer. Clin Oncol. 1990;2:309-312.

116. DiSaia PJ, Odicino F, Grosen EA, Cowan B, Pecorelli S, Wile AG. Hormone replacement therapy in breast cancer. Lancet. 1993;342:1232.

117. Powles TJ, Hickish T, Casey S, O'Brian M. Hormone replacement therapy after breast cancer. Lancet. 1993;341:60-61.

118. Wile AG, Opfell RW, Margileth DA. Hormone replacement therapy in previously treated breast cancer patients. Am J Surg. 1993;165:372-375.

119. Eden JA, Bush T, Nand S, Wren BG. A case-controlled study of combined continuous oestrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause. 1995;2:67-72.

120. Vassilopoulou-Sellin R, Zolinski C. Estrogen replacement therapy in women with breast cancer: a survey of patient attitudes. Am J Med Sci. 1992;304(3):145-149.

121. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. Engl J Med. 1975;293:1167-1170.

122. Smith DC, Prentice R, Thompson DJ, et al. Association of exogenous estrogen and endometrial carcinoma. Engl J Med. 1975;293:1164-1167.

123. Baker DP. Estrogen-replacement therapy in patients with previous endometrial carcinoma. Compr Ther. 1990;16(1):28-35.

124. Persson I, et al. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy — long term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327-332.

125. Schwartzbaum J, et al. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol. 1987;126:851-860.

126. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. Engl J Med. 1985;313:1038-1043.

127. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. Engl J Med. 1996;335:453-461.

128. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: A prospective study. Br Med J. 1988;297:519-522.

129. Falkeborn M, Persson I, Terent A, Adami HO, Lithell H, Bergstrom R. Hormone replacement therapy and the risk of stroke. Follow-up of a population-based cohort in Sweden. Arch Intern Med. 1993;153:1201-1209.

130. Finucane FF, Madams JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users. Results from a national cohort. Arch Intern Med. 1993;153:73-79.

131. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet. 1996;348:983-987.

132. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977-980.

133. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348:981-983.

134. Devor M, Barrett-Connor E, Renvall M, Feigel D Jr, Ramsdell J. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med. 1992;92:275-282.

Patient Handout

Women develop heart disease 10 years later than men

• Most women are more afraid of breast cancer than of heart disease and stroke.
• In reality, 1 in 25 women dies from breast cancer, while almost 1 in 2 dies from heart disease.

What is a risk factor?

• Risk factors are conditions or activities that increase your likelihood of developing heart disease.

• There are a number of risk factors associated with heart disease and stroke.

• Cigarette smoking

• High cholesterol

• Physical inactivity

• Overweight and obesity

• Diabetes mellitus

It is possible to prevent heart disease to some extent by reducing risk factors

• High blood cholesterol, physical inactivity, and being overweight are particular problems for women.
• For ages 35 to 44, the mean total blood cholesterol of women is 195 mg/dL, but between ages 45 and 64 the average rises from 217 mg/dL to 235 mg/dL.
• A higher percentage of women than men have a total blood cholesterol of 200 mg/dL or higher beginning at age 50. Women lose the protective effect of estrogen at menopause
• As menopause approaches, estrogen production slows.
• Estrogen, as part of hormone replacement therapy, helps in reversing the lipid changes that occur with menopause.
• Estrogen decreases the undesirable LDL cholesterol and increases the beneficial HDL cholesterol.
• Studies suggest that estrogen reduces your risk of developing heart disease by as much as half.