There is ample reason for the study of this controversial question, because millions of women have survived this disease. Approximately 175,000 new breast cancer cases are diagnosed annually in the United States, and the overall disease-free survival at 5 years is in excess of 70%. The breast cancer survivors are the largest group of former cancer patients in the United States. Furthermore, the recent broadening of indications of adjuvant chemotherapy has created a well-recognized increase in the numbers of premenopausal patients (ages 25–50 years) who are rendered prematurely menopausal by the effect of cytotoxic drugs on their ovarian function. ¹

In the last 3 decades, two demographic trends have heightened awareness concerning menopause and its health consequences. First and foremost, women are living longer. Life expectancy for U.S. women in 1900 was age 45,[1] and now it is close to 80 years of age. Tens of millions of women are spending fully 40% of their life after menopause. More women than ever will enter the menopausal years in the United States in the next decade, as millions of baby boomers, those born after World War II, enter their 50s. The proportion of all U.S. women older than 45 years of age will grow from 34% in 1995 to 43% in the year 2020. Thus, a large number of women are likely to have a history of breast cancer treatment and, at the same time, be potential candidates for HRT.

During the last 30 years, there has been an overwhelming number of observational studies demonstrating that HRT protects against ischemic heart disease, osteoporosis, deterioration in cognitive function, colorectal cancer, the reduced incidence of macular degeneration, as well as providing a decided improvement in quality-of-life, such as vasomotor symptoms, urogenital atrophy, insomnia, and general well being. 

Cardiovascular disease:

Observational studies suggest a 50% reduction in the risk of serious cardiovascular incidents among healthy postmenopausal women taking oral estrogen. ² Stampfer et al. ³ evaluated postmenopausal estrogen therapy and cardiovascular disease in the Nurses’ Health Study with a 10-year follow-up. Current users of HRT accounted for approximately 22% of the total follow-up time of 337,854 person-years. There was a reduction in age-adjusted relative risk of fatal cardiovascular disease in current users of HRT that was approximately half that of women who had never used estrogen, with a relative risk of 0.51 p < 0.0001. The authors of the Postmenopausal Estrogen/Progestin Interventions trial also examined this issue. ⁴ They found, as in numerous previous studies, that unopposed estrogen decreased the risk of cardiovascular disease. In the Postmenopausal Estrogen/Progestin Interventions trial, estrogen given with medroxyprogesterone acetate or micronized progesterone HRT were both associated with lower fibrinogen levels and improved lipid profiles.

Grodstein et al. ⁵ evaluated the effect of combined estrogen and progestin use and the risk of cardiovascular disease in the Nurse’s Health Study. Among the 59,337 women enrolled, there were 770 casualties of myocardial infarction or deaths from coronary artery disease. There was a marked decrease in the risk of major coronary artery disease among women who took estrogen with progestin as compared with the risk of women who did not use hormones. The multivariate adjusted relative risk was 0.39 (95% confidence interval [CI] 0.19–0.78).

Alzheimer disease:

Because of an ever increasing number of elder people, Alzheimer disease has emerged as a major health problem. After the age of 65 years, the prevalence of dementia and Alzheimer disease doubles every 5 years; thus, 30% to 50% of women older than 83 years may have dementia of some sort.

Laboratory studies suggest that estrogen may affect Alzheimer disease through several mechanisms. Estrogen has been shown to improve regional cerebral blood flow and to increase glucose utilization. It can also stimulate neurite growth and synapse formation in vitro. Under some circumstances, estrogen may modify neural sensitivity to neurotrophin and play a role in the reparative neuronal response to injury. One key histologic feature of Alzheimer disease is the deposition of [beta]-amyloid protein in cores of neuritic plaques. Estrogen may promote the breakdown of the amyloid precursor protein to fragments less likely to accumulate as [beta]-amyloid. Acetylcholine is a key neurotransmitter in learning and memory. Estrogen affects several neurotransmitter systems including the cholinergic system. Finally, estrogen may modify inflammatory responses postulated to participate in neuritic plaque formation. ⁸

Tang et al. 9 examined the effect of a history of estrogen use on the development of Alzheimer disease among 1,124 women. These were subjects initially free of Alzheimer disease, Parkinson disease, and stroke and were part of a longitudinal study of aging and health in a New York community. Overall, 12.5% women reported taking estrogen after the onset of menopause. The age of onset of Alzheimer disease was significantly later in women who had taken estrogen than in those who did not (78 years versus 73 years). Even after adjustment for differences in education and ethnic origin, the relative risk of Alzheimer disease was significantly reduced in estrogen users versus nonusers; 0.4, with the 95% CI 0.22 to 0.85. Even among postmenopausal women who are not demented, estrogen replacement therapy may help to maintain cognitive function. 10 Estrogen appears to have a specific effect on verbal memory skills in healthy postmenopausal women. ^11,12

The emotional, physical, social, and financial costs to patients, families, caregivers, and society are tremendous. The estimated total cost of Alzheimer disease in 1991 was estimated to be $173,932 per case. The estimated prevalence cost for both men and women for that year was $67.3 billion. ¹³ The economic cost of care alone is greater than the cost of care for heart disease and cancer combined. If the use of estrogen could delay the onset of Alzheimer disease by a few years, there would be a substantial saving in both emotional and financial costs.

Colorectal cancer.

There have been more than 20 retrospective studies of the risk of colon cancer and HRT, with more than 70% of these reports illustrating a statistically significant reduction in the incidence with users versus nonusers. The biologic mechanism that effects this protection is thought to be based on the action of exogenous estrogen in reducing the concentration of bile acids, and its direct action on the colon mucosa. It has been demonstrated that bile acid concentrations are higher in colon cancer cases than in control subjects, and that estrogen decreases bile acid synthesis and secretion.¹⁴ Estrogen receptors are present in both normal and cancerous colon mucosal cells, and there is laboratory evidence to suggest that estrogen may inhibit the growth of colon cancer cells. ¹⁵

Calle et al. ¹⁶ investigated the relationship between postmenopausal estrogen use and fatal colorectal cancer in a large prospective study of U.S. adults. Eight hundred seventy-nine patients with colon cancer were compared with 421,476 noncase subjects. Ever-use of estrogen replacement therapy was associated with a significantly decreased risk of fatal colon cancer (relative risk = 0.71); 95% CI 0.61 to 0.83. The reduction in risk was strongest among current users (relative risk = 0.55; 95% CI = 0.40–0.76), as compared with former estrogen users. There was a significant trend of decreasing risk with increasing years of estrogen use among all users (p = 0.0001). Those women who used estrogen for 1 year or less had a relative risk = 0.81, whereas users of 11 years or more had a relative risk of 0.54 (95% CI = 0.39–0.76). These associations were not altered in multivariate analyses controlling for age, race, parental history of colon cancer, body mass index, exercise, parity, type of menopause, age of menopause, oral contraceptive pill use, aspirin use, and smoking.

Analysis of the incidence and mortality of a cohort of 22,597 Swedish women prescribed replacement hormones and followed for 13 years noted a 40% reduction in the risk estimate of colon cancer among those who received an estradiol–progestin compound. ¹⁷

RESULTS

The distribution of breast cancer stage among the cases was as follows: in situ, 17 of 125 (13.6%); stage I, 52 of 125 (41.6%); stage II, 27 of 125 (21.6%); stage III, 10 of 125 (8%); stage IV, 1 of 125 (0.8%); unknown, 18 of 125 (14.4%). Ninety-eight percent of the cases (123/125) received systemic estrogen, and 90 of 125 (72%) received a progestational agent. The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0–401 months). The median age of the case and control subjects at the time of breast cancer diagnosis was 51.9 and 52.1 years, respectively (Table 1).

& Table 1                                              

Kaplan–Meier survival analysis of death from all causes indicated a survival advantage for the breast cancer survivors who received HRT over the non-HRT users 15 years after breast cancer diagnosis, 88% versus 63%, respectively (p = 0.003) (Fig. 1). Similar survival analysis inclusive only of those cases with a known breast cancer stage (N = 107) and their matched controls (N = 313) demonstrated the same significant survival advantage to the case subjects in comparison to the control subjects 15 years after diagnosis of breast cancer 85% versus 56%, respectively (p = 0.01) [15/100 VERSUS 44/100 deaths].  When the entire study group was considered, there was an almost 70% reduction in the risk of death among the HRT users than the control subjects, odds ratio 0.28 (95% CI 0.11–0.71). [This study controls for contravening variable:  The HRT users have been matched with the non-users to control for life style and other factors which would distort the results]. 

& Fig. 1                                                  

When secondary malignancies, excluding breast cancer, were evaluated both among the cases and controls, six endometrial cancers were present among the cases but none was identified in the control group.

Our series of patients and this cohort study do not suggest that HRT is associated with compromise in survival. This analysis indicated a survival advantage for survivors of breast cancer who elected HRT, with a 70% reduction in the risk of death. A strength of this analysis is that these findings are consistent with a previous cohort analysis consisting of 41 cases and 82 controls.²² This report is not inclusive of any of the cases or controls used in the previous study, and unlike the previous report, an adjustment was made in the selection of controls to ensure that each control survived as long as the period during which the matched case delayed HRT after her breast cancer diagnosis. This ensured that there would not be survival bias in favor of the survivors of breast cancer who delayed the initiation of HRT. It is unfortunate that we were unable to match based on other prognostic variables such as ER status, her2-neu status, breast cancer treatment, and duration of use of tamoxifen in the two groups. The inability to perform more detailed matching is a limitation of this analysis.

The reduction in the risk of death is not likely related to a therapeutic effect of HRT on microscopic or dormant breast cancer cells. The benefits of HRT both through the quality of life of postmenopausal women and the prevention of serious disease processes has been firmly established. There has not been a large prospective randomized study of survivors of breast cancer to answer the question of risk associated with the use of HRT. Even if one could overcome the emotional objections to such a study, its execution would require generous funding and large numbers of patients (e.g., at least 5,000). Compliance, especially for the placebo group, would be a major concern. This makes such a trial unlikely and certainly not helpful to the clinician in the near future. In the interim, as practicing clinicians, can we avoid the responsibility of thoroughly informing our patients of the benefits, as well as the potential risks of HRT [being sued], and then allowing them to decide on the course of action?  Is it proper to continue our practice of categorically prohibiting all patients with breast cancer from using HRT?

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