I. A decision tree for the use of estrogen replacement therapy or hormone replacement therapy in postmenopausal women: consensus opinion of The North American Menopause Society.

OBJECTIVE: Menopause is associated with physiologic changes that may have negative effects on quality of life in some women and/or that may increase morbidity and mortality secondary to osteoporosis and/or coronary heart disease. Estrogen replacement therapy (ERT) and combined estrogen/progestogen therapy (hormone replacement therapy [HRT]) play an important role in reducing these negative effects.

The North American Menopause Society (NAMS) sought to develop treatment algorithms that could assist the clinician in deciding whether to recommend ERT/HRT to postmenopausal women. DESIGN: NAMS held a closed conference of experts to develop a decision tree that outlined the rational use of ERT/HRT in postmenopausal women on the basis of risks versus benefits.The proceedings of the conference were used to assist the NAMS Board of Trustees in developing this consensus opinion of the Society. RESULTS: On the basis of the conference proceedings, NAMS developed three algorithms for the clinician to use as a tool in deciding whether to recommend ERT/HRT to a woman who is postmenopausal: (1) menopause-related symptoms, (2) cardiovascular risk, and (3) osteoporosis risk. CONCLUSIONS: The goal of ERT/HRT is to enhance women's quality of life as well as to reduce the risks of death and disability associated with osteoporosis and coronary heart disease. The decision to initiate ERT/HRT must be individualized according to each woman's needs. This decision tree for ERT/HRT presents a rational approach to decision making on the basis of the principles of care; details of specific therapeutic interventions will change as data from clinical trials are presented.

 
II. Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones.

Tworoger SS , et al.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

BACKGROUND: Sex hormone concentrations are associated with breast cancer risk among women not using postmenopausal hormones (PMH); however, whether a relationship exists among PMH users is unknown. Therefore, we conducted a prospective, nested case-control study within the Nurses' Health Study (NHS) cohort to examine the association between plasma sex hormone concentrations and postmenopausal breast cancer among women using PMH at blood collection. METHODS: Blood samples were collected from 1989 to 1990. During follow-up through May 31, 2000, 446 women developed breast cancer and were matched by age, date and time of day of blood collection, and fasting status to 459 control subjects (PMH users) who did not develop cancer. We used conditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). We compared hormone concentrations of the 459 control subjects with those of 363 postmenopausal NHS participants not taking PMH. All statistical tests were two-sided. RESULTS: PMH users had statistically significantly higher estradiol, free estradiol, sex hormone-binding globulin, and testosterone, and lower free testosterone concentrations than non-PMH users. Among PMH users, we found modest associations with breast cancer risk when comparing the highest versus lowest quartiles of free estradiol (RR = 1.7, 95% CI = 1.1 to 2.7; P(trend) = .06), free testosterone (RR = 1.6, 95% CI = 1.1 to 2.4; P(trend) = .03), and sex hormone-binding globulin (RR = 0.7, 95% CI = 0.5 to 1.1; P(trend) = .04), but not of estradiol or of testosterone. However, estradiol and free estradiol were statistically significantly positively associated with breast cancer risk among women older than 60 years (RR = 2.8, 95% CI = 1.5 to 5.0; P(trend) = .002 and 2.6, 95% CI = 1.4 to 4.7; P(trend) = .001, respectively) and among women with a body mass index of less than 25 kg/m2 (RR = 1.8, 95% CI = 1.1 to 3.1, P(trend) = .01 and 2.4, 95% CI = 1.4 to 4.0, P(trend) = .003, respectively). CONCLUSION: Although women using PMH have a different hormonal profile than those not using PMH, plasma sex hormone concentrations appear to be associated with breast cancer risk among PMH users.

III. Postmenopausal hormone replacement therapy: scientific review.

Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD.

Oregon Health and Science University, Mail Code BICC 504, 3181 SW Sam Jackson Park Rd, Portland, OR 97201, USA. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

CONTEXT: Although postmenopausal hormone replacement therapy (HRT) is widely used in the United States, new evidence about its benefits and harms requires reconsideration of its use for the primary prevention of chronic conditions. OBJECTIVE: To assess the benefits and harms of HRT for the primary prevention of cardiovascular disease, thromboembolism, osteoporosis, cancer, dementia, and cholecystitis by reviewing the literature, conducting meta-analyses, and calculating outcome rates. DATA SOURCES: All relevant English-language studies were identified in MEDLINE (1966-2001), HealthSTAR (1975-2001), Cochrane Library databases, and reference lists of key articles. Recent results of the Women's Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study (HERS) are included for reported outcomes. STUDY SELECTION AND DATA EXTRACTION: We used all published studies of HRT if they contained a comparison group of HRT nonusers and reported data relating to HRT use and clinical outcomes of interest. Studies were excluded if the population was selected according to prior events or presence of conditions associated with higher risks for targeted outcomes. DATA SYNTHESIS: Meta-analyses of observational studies indicated summary relative risks (RRs) for coronary heart disease (CHD) incidence and mortality that were significantly reduced among current HRT users only, although risk for incidence was not reduced when only studies that controlled for socioeconomic status were included. The WHI reported increased CHD events (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02-1.63). Stroke incidence but not mortality was significantly increased among HRT users in the meta-analysis and the WHI. The meta-analysis indicated that risk was significantly elevated for thromboembolic stroke (RR, 1.20; 95% CI, 1.01-1.40) but not subarachnoid or intracerebral stroke. Risk of venous thromboembolism among current HRT users was increased overall (RR, 2.14; 95% CI, 1.64-2.81) and was highest during the first year of use (RR, 3.49; 95% CI, 2.33-5.59) according to a meta-analysis of 12 studies. Protection against osteoporotic fractures is supported by a meta-analysis of 22 estrogen trials, cohort studies, results of the WHI, and trials with bone density outcomes. Current estrogen users have an increased risk of breast cancer that increases with duration of use. Endometrial cancer incidence, but not mortality, is increased with unopposed estrogen use but not with estrogen with progestin. A meta-analysis of 18 observational studies showed a 20% reduction in colon cancer incidence among women who had ever used HRT (RR, 0.80; 95% CI, 0.74-0.86), a finding supported by the WHI. Women symptomatic from menopause had improvement in certain aspects of cognition. Current studies of estrogen and dementia are not definitive. In a cohort study, current HRT users had an age-adjusted RR for cholecystitis of 1.8 (95% CI, 1.6-2.0), increasing to 2.5 (95% CI, 2.0-2.9) after 5 years of use. CONCLUSIONS: Benefits of HRT include prevention of osteoporotic fractures and colorectal cancer, while prevention of dementia is uncertain. Harms include CHD, stroke, thromboembolic events, breast cancer with 5 or more years of use, and cholecystitis.

 
IV. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women.

Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE.

Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

BACKGROUND: Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopausal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+/PR+], and 39 ER-negative and PR-negative [ER-/PR-] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors. RESULTS: We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with ER+/PR+ tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease. CONCLUSION: Circulating levels of sex steroid hormones may be most strongly associated with risk of ER+/PR+ breast tumors.

V. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.

Key T, Appleby P, Barnes I, Reeves G;
Endogenous Hormones and Breast Cancer Collaborative Group .

Cancer Research U.K. Epidemiology Unit, University of Oxford, Radcliffe Infirmary, Oxford, UK.

BACKGROUND: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. METHODS: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. RESULTS: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. CONCLUSION: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.

 VI. Hormone replacement therapy and breast cancer: revisiting the issues.

DeGregorio MW, Taras TL.

Department of Internal Medicine, University of California, Sacramento 95817, USA. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

OBJECTIVE: To assess current ideas about the benefits and risks of estrogen and hormone replacement therapy (ERT/HRT) in postmenopausal women. DATA SOURCES: MEDLINE searches, supplemented by various texts, of the literature on HRT, ERT, and selective estrogen receptor modulators (SERMs): tamoxifen, toremifene, and raloxifene. DATA SYNTHESIS: HRT is primarily used for improving quality of life in women suffering from vasomotor symptoms associated with menopause. HRT is beneficial in postmenopausal women for preventing cardiovascular disease, osteoporosis, and Alzheimer's disease. Review of meta-analyses of clinical trials showed that ERT/HRT ever-users (patients who have ever used ERT/HRT) did not have an increased risk of breast cancer, but current users did have an increased risk, with some studies reporting increasing risk with duration of ERT. No relationship was found between dose or the addition of progestin to ERT and increased breast cancer risk. Overall breast cancer mortality rates associated with HRT were decreased in current users. In general, HRT does not increase the risk of breast cancer in women with a family history of the disease, compared with those without a family history. New HRT strategies that could potentially prevent breast cancer are now being developed. The SERMs tamoxifen and toremifene appear to have positive clinical effects on bone and serum lipids; they are currently being investigated for use as breast cancer chemopreventive agents. Raloxifene, a new SERM used for the prevention of osteoporosis, is an alternative for women who cannot tolerate HRT. Unfortunately, these SERMS have anti-estrogenic effects and thus cause vasomotor adverse effects such as hot flashes and vaginal dryness. In addition, SERMs do not protect against heart disease or prevent osteoporosis as well as does HRT. CONCLUSION: Presently, SERMs will not become first-line HRT, as the positive effects of ERT/HRT may outweigh any potentially increased risk of breast cancer. The development of new agents with pharmacodynamic profiles similar to that of ERT/HRT but lacking its adverse effects would be greatly beneficial for postmenopausal women.

 VII. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

 VIII. Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

Roy JA, Sawka CA, Pritchard KI.

Division of Medical Oncology/Haematology, Toronto-Sunnybrook Regional Cancer Centre, Ontario, Canada.

PURPOSE: To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD: A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS: None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION: In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.

IX. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).

Kaaks R , et al.

Nutrition and Hormones Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

BACKGROUND: Contrasting etiologic hypotheses about the role of endogenous sex steroids in breast cancer development among premenopausal women implicate ovarian androgen excess and progesterone deficiency, estrogen excess, estrogen and progesterone excess, and both an excess or lack of adrenal androgens (dehydroepiandrosterone [DHEA] or its sulfate [DHEAS]) as risk factors. We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort to examine associations among premenopausal serum concentrations of sex steroids and subsequent breast cancer risk. METHODS: Levels of DHEAS, (Delta4-)androstenedione, testosterone, and sex hormone binding globulin (SHBG) were measured in single prediagnostic serum samples from 370 premenopausal women who subsequently developed breast cancer (case patients) and from 726 matched cancer-free control subjects. Levels of progesterone, estrone, and estradiol were also measured for the 285 case patients and 555 matched control subjects who had provided information about the day of menstrual cycle at blood donation. Conditional logistic regression models were used to estimate relative risks of breast cancer by quartiles of hormone concentrations. All statistical tests were two-sided. RESULTS: Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P(trend) = .01), androstenedione (OR for highest versus lowest quartile = 1.56, 95% CI = 1.05 to 2.32; P(trend) = .01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P(trend) = .10) but not SHBG. Elevated serum progesterone concentrations were associated with a statistically significant reduction in breast cancer risk (OR for highest versus lowest quartile = 0.61, 95% CI = 0.38 to 0.98; P(trend) = .06). The absolute risk of breast cancer for women younger than 40 followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone versus 1.5% for those in the lowest quartile; for the highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively. Breast cancer risk was not statistically significantly associated with serum levels of the other hormones. CONCLUSIONS: Our results support the hypothesis that elevated blood concentrations of androgens are associated with an increased risk of breast cancer in premenopausal women.

X. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women.

Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, Koenig KL, Shore RE, Kim MY, Pasternack BS, Toniolo P.

Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University School of Medicine, NY 10010, USA.

The authors examined the relation between postmenopausal serum levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) and subsequent risk of breast cancer in a case-control study nested within the New York University Women's Health Study cohort. A specific objective of their analysis was to examine whether androgens had an effect on breast cancer risk independent of their effect on the biologic availability of estrogen. A total of 130 cases of breast cancer were diagnosed prior to 1991 in a cohort of 7,054 postmenopausal women who had donated blood and completed questionnaires at a breast cancer screening clinic in New York City between 1985 and 1991. For each case, two controls were selected, matching the case on age at blood donation and length of storage of serum specimens. Biochemical analyses were performed on sera that had been stored at -80 degrees C since sampling. The present report includes a subset of 85 matched sets, for whom at least 6 months had elapsed between blood donation and diagnosis of the case. In univariate analysis, testosterone was positively associated with breast cancer risk (odds ratio (OR) for the highest quartile = 2.7, 95% confidence interval (CI) 1.1-6.8, p < 0.05, test for trend). However, after including % estradiol bound to sex hormone-binding globulin (SHBG) and total estradiol in the statistical model, the odds ratios associated with higher levels of testosterone were considerably reduced, and there was no longer a significant trend (OR for the highest quartile = 1.2, 95% CI 0.4-3.5). Conversely, breast cancer risk remained positively associated with total estradiol levels (OR for the highest quartile = 2.9, 95% CI 1.0-8.3) and negatively associated with % estradiol bound to SHBG (OR for the highest quartile = 0.05, 95% CI 0.01-0.19) after adjustment for serum testosterone levels. These results are consistent with the hypothesis that testosterone has an indirect effect on breast cancer risk, via its influence on the amount of bioavailable estrogen. No evidence was found of an association between DHEAS and risk of breast cancer in postmenopausal women.

XI. Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study.

Zeleniuch-Jacquotte A, Shore RE, Koenig KL, Akhmedkhanov A, Afanasyeva Y, Kato I, Kim MY, Rinaldi S, Kaaks R, Toniolo P.

Department of Environmental Medicine, New York University School of Medicine, 650 First Avenue, New York, NY 10016, USA. This e-mail address is being protected from spambots. You need JavaScript enabled to view it

We assessed the association of sex hormone levels with breast cancer risk in a case-control study nested within the cohort of 7054 New York University (NYU) Women's Health Study participants who were postmenopausal at entry. The study includes 297 cases diagnosed between 6 months and 12.7 years after enrollment and 563 controls. Multivariate odds ratios (ORs) (95% confidence interval (CI)) for breast cancer for the highest quintile of each hormone and sex-hormone binding globulin (SHBG) relative to the lowest were as follows: 2.49 (1.47-4.21), P(trend)=0.003 for oestradiol; 3.24 (1.87-5.58), P(trend)<0.001 for oestrone; 2.37 (1.39-4.04), P(trend)=0.002 for testosterone; 2.07 (1.28-3.33), P(trend)<0.001 for androstenedione; 1.74 (1.05-2.89), P(trend)<0.001 for dehydroepiandrosterone sulphate (DHEAS); and 0.51 (0.31-0.82), P(trend)<0.001 for SHBG. Analyses limited to the 191 cases who had donated blood five to 12.7 years prior to diagnosis showed results in the same direction as overall analyses, although the tests for trend did not reach statistical significance for DHEAS and SHBG. The rates of change per year in hormone and SHBG levels, calculated for 95 cases and their matched controls who had given a second blood donation within 5 years of diagnosis, were of small magnitude and overall not different in cases and controls. The association of androgens with risk did not persist after adjustment for oestrone (1.08, 95% CI=0.92-1.26 for testosterone; 1.15, 95% CI=0.95-1.39 for androstenedione and 1.06, 95% CI=0.90-1.26 for DHEAS), the oestrogen most strongly associated with risk in our study. Our results support the hypothesis that the associations of circulating oestrogens with breast cancer risk are more likely due to an effect of circulating hormones on the development of cancer than to elevations induced by the tumour. They also suggest that the contribution of androgens to risk is largely through their role as substrates for oestrogen production.

XII. Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

Roy JA, Sawka CA, Pritchard KI.

Division of Medical Oncology/Haematology, Toronto-Sunnybrook Regional Cancer Centre, Ontario, Canada.

PURPOSE: To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD: A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS: None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION: In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.