The Risk of Breast Cancer Associated with Oral Contraception and Hormone Replacement Therapy Leon Speroff, MD Professor of Obstetrics and Gynecology Oregon Health Sciences University Portland, Oregon
ral contraception and hormone replacement therapy can, in my view, be legitimately regarded as components of preventive health care for women. An important obstacle to achieving the benefits of these two health care programs is the maintenance of good compliance. Despite the fact that oral contraception is highly effective, hundreds of thousands of unintended pregnancies occur each year in the United States because of poor compliance. It is also well recognized that only about onethird of postmenopausal women continue their regimen of hormone replacement beyond 1 year's time. Compliance is an area in which personal behavior, biology, and pharmacology come together. There are three major factors that affect compliance: fears and concerns regarding serious side effects, the experience of minor side effects, and nonmedical issues such as inadequate instructions. The fear of cancer, especially breast cancer, plays an important role in noncompliance. Indeed, the actual fear of the possibility of cancer is a more important patient response and consideration than the precise knowledge regarding the presence or absence of an association with any given treatment. The clinician's ability to deal with this fear, however, requires a good understanding of available and current data. This is an era of informed choice by the patient. Patients deserve to know the facts and need help in dealing with the state of the art and the uncertainty. But there is no doubt that patients are influenced in their choices by their clinician's advice and attitude. Although the role of a clinician is to provide the education necessary for the patient to make proper choices, one should not lose sight of the powerful influence exerted by the clinician in the choices ultimately made. Because of the above considerations, it is very important to assess the state of knowledge regarding the risk of breast cancer with oral contraception and hormone replacement therapy. This is the information the clinician needs to bring to the individual patient-clinician encounter.
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ORAL C O N T R A C E P T I O N A N D THE RISK OF BREAST C A N C E R Until the mid-1980s, there was a consistent absence of any epidemiologic data linking oral contraception with an increased risk of breast cancer. Over the last several years, several investigators reported a shift from negative results to positive results. It was suggested that this shift was due to a change in usage of oral contraception, from use in the 1960s by older w o m e n to space out children, to use in the 1980s by y o u n g w o m e n to delay an initial pregnancy. Because a full-term p r e g n a n c y early in life protects against breast cancer, it is an important possibility that participants in these studies are, for the first time, fulfilling specific conditions that might predispose t h e m to an increased risk of breast cancer. It is possible that this is the reason w h y the major cohort studies (the Royal College of General Practitioners Study, the Oxford Family Planning Association Study, the Walnut Creek Study, and the Nurses' Health Study) that recruited participants in the 1960s and 1970s have failed to find any significant differences in breast cancer rates b e t w e e n users and nonusers of oral contraception. 1-5 Over the last decade, therefore, case-control studies have focused on the use of oral contraception early in life, for long durations, and to delay a first, full-term pregnancy. Because the cohort of w o m e n w h o have used oral contraception in this fashion is just n o w beginning to reach the ages of postmenopausal breast cancer, the studies have had to examine the risk of breast cancer diagnosed before age 45 (which is only 13% of all breast cancers). Some of these recent case-control studies have indicated an overall increased relative risk of early, p r e m e n o p a u s a l breast cancer, 6-11 whereas others indicated no increase in overall risk. ~2-21 Examining use before a first full-term pregnancy does not yield consistent results. Some studies indicate an increased risk for breast cancer, 22 but most do n o t . 6"1°A1"16'18-2°'23 These inconsistent conclusions may reflect epidemiologic difficulties. For example, in the Oxford Family Planning Association study, the relative risk for use before a first full-term pregnancy was 2.59; however, only 2% of their patients u s e d oral contraception before a first full-term pregnancy.17 For use before age 25, the majority of studies, but not all, indicated no increased risk of breast cancer. The most impressive finding indicates a link in most s t u d i e s , 7"9"1°'17AS"z2 but not all, 19'2° of early breast cancer before age 40 in w o m e n w h o used oral contraception for long durations of time. The Centers for Disease Control (CDC) Cancer and Sex H o r m o n e (CASH) study is the largest case-control s t u d y on the s u b j e c t . 24-26 No overall increased risk of breast cancer was f o u n d in w o m e n first using oral contraceptives before the age of 20 with a duration of use greater than 4 years, or before the age of 25 with a duration of use greater than 6 years, or with greater than 4 years' use before a first pregnancy. In addition, no overall increased risk of breast cancer was found a m o n g any subgroups of users including w o m e n with benign breast disease or a family history of breast cancer. There was no increased risk associated with any specific type of oral contraceptive or progestin-only pills, or the use of two or more types. In addition, there was no increased risk associated with any specific progestin or estrogen c o m p o n e n t and, most importantly, it was d e m o n s t r a t e d that long-term use (15 or more years) was not associated with an increased risk of breast cancer. Thus far, the CDC study has f o u n d no evidence for a latent effect on breast cancer risk through age 54. 27 The CDC has recently reexamined their data to determine w h e t h e r oral contraceptive use had different effects on the risk of breast cancer diagnosed at different ages. 28 This analysis indicated that oral contraceptive use slightly increased the risk of breast cancer diagnosed u n d e r the age of 35
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and had no effect on women diagnosed from age 35-44; in women diagnosed from age 45-54, oral contraceptive use appeared to decrease the risk of breast cancer. However, these estimates were of borderline statistical significance. The protection that oral contraceptive use appeared to provide to older women is a more convincing argument because it was supported by several dose-response relationships (age with first use and time since first and last use). The elevated risk among the women with early breast cancer is a more tenuous conclusion, not strengthened by supporting doseresponse patterns. The crucial question is: As studies gain more statistical power, will they confirm a slightly increased risk for premenopausal breast cancer or will the present suggestion of an increased risk disappear? For example, an early report from New Zealand indicated an increased relative risk for premenopausal breast cancer and, as the study continues, this relative risk is moving closer and closer to 1.0. 29 Further comfort can be derived from the United States national cancer surveillance data. 3° The increase in breast cancer in American women is in older women, those who did not have the opportunity to use oral contraception. In women under 56 years of age, there has been no change in the age-specific breast cancer rates from 1950-1985.
Conclusion
The following conclusions can be drawn from the currently available epidemiologic data: 1. Long-term use of oral contraception during the reproductive years is not associated with a significant increase in the risk of breast cancer after age 45. Indeed, there is the possibility, as suggested by the recent CDC report, that exposure to early contraception confers some degree of protection against postmenopausal breast cancer. 2. There has been consistent failure to demonstrate an increased risk of breast cancer with oral contraceptive use in women with positive family histories of breast cancer or in women with proven benign breast disease. 25"31 3. There is the possibility that a young subgroup of women who use oral contraception early and for a long time (4 years or more) has a slightly increased risk of breast cancer before the age of 45, a relative risk of less than 1.5. Keep in mind that this possibility is derived from studies of older, higherdose oral contraception. There are at least two reasons that make continuing studies on this issue important. First is the aging of the cohort of users and the need to both increase the statistical power of the current studies and to determine the emerging risk as these women age. Second, the possibility of greater safety with lower dosage must be documented. When adding up the benefits of oral contraception, the possible slight increase in risk of breast cancer is far outweighed by positive effects on our public health. But the impact on public health is of little concern during the private clinician-patient interchange in the office. Here personal risk receives highest priority; fear of cancer is a motivating force, and compliance with effective contraception requires accurate information. I believe it is appropriate to state that there is no definitive evidence demonstrating a link between breast cancer and oral contraception. On the other hand, patients deserve to know about our concern and about the findings regarding long duration of use and the possible increased risk of early, premenopausal breast cancer. As long as the inconsistencies exist in the epidemiologic evidence, the clinician is justified in being optimistic, stating that risk is possible but has not been proven. WHI Vol. 2, No. 2 Summer 1992
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H O R M O N E REPLACEMENT THERAPY A N D THE RISK OF BREAST CANCER A recent study from Uppsala, Sweden concluded that postmenopausal estrogen use was associated with a slight increase in the risk of breast cancer (relative risk 1.1), and that there was a relationship with duration of use; the relative risk reached 1.7 after 9 years. 32 This increased risk was associated only with the use of estradiol (in a dose approximately double the current standard in the United States). The authors indicated that this investigation was a case-cohort type of epidemiologic study, prospective in the nature of its follow-up. The impression, strongly given, was that the cohort was large, consisting of 23,244 women. Actually the cohort consisted of the 653 w om en who answered a questionnaire sent to 1 in 30 of the 23,244 women. One should note immediately that 11% did not return the questionnaire, introducing the question of selection bias. The results in this subgroup were extrapolated to the large group of women. The authors correctly indicated that there was a trend toward increasing relative risk with duration of use (in other words, it was not statistically significant). The confidence intervals included 1.0 and, by definition, this is not statistically significant. The indication of increased risk with sequential estrogen-progestin was based on only ten wom en with breast cancer, and the confidence interval was impressively wide: 0.9-22.4. A further indication that bias may have influenced the results can be found in another publication by the same Uppsala group utilizing the same cohort. They concluded that women using estrogen who develop breast cancer have a more favorable course with a higher survival rate. 33 In that report, selection bias and surveillance bias were very possible. They further reported, in yet another publication, that estrogen users more commonly had a high risk pattern on mammography, another possible confounding variable. 34 A case-control study from Denmark that also utilized questionnaires to obtain information from both the cases and controls concluded that there was a slightly increased risk of breast cancer associated with sequential estrogen and progestin therapy. 3s This study contains limitations similar to the Uppsala study (small numbers of cases and statistically nonsignificant conclusions). Earlier studies indicated higher risks in special subcategories such as women with benign breast disease, long duration of use, or natural versus surgical menopause. 36-4s These studies suffered several statistical problems: lack of appropriate controls, differences in doses, and small numbers. The CASH study of the CDC is a large, population-based, case-control study from eight geographic locations. The CASH study has not detected an overall increased risk of breast cancer with postmenopausal estrogen use and has detected no relationship with duration of use up to 20 years or longer. 46 There were positive findings in certain subgroups, most notably in w om en with menopause because of bilateral oophorectomy. However, the confidence intervals in these subgroup analyses include 1.0 and therefore the conclusions did not reach statistical significance. The latest report from the Nurses' Health Study represents 10 years of follow-up (1976-1986). 47 During that period, 722 cases of breast cancer were identified among more than 20,000 women. The analysis revealed that w om en who had used replacement estrogen in the past (even for 10 or more years) were not at increased risk of breast cancer. However, the relative risk for current users was 1.36 (confidence interval 1.11-1.67). An earlier report from this cohort (based on only 4 years of follow-up) was totally negative in terms of an association between current use of estrogen replacement and risk of breast cancer. 48 The investigators believe their current finding is within the confidence interval of the earlier analysis. Compared with never-users, cur66
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rent users were slightly more likely to have certain risk factors (history of benign breast disease, nulliparity, use of alcohol). However, adjustment for several of these risk factors only minimally reduced the relative risk for current use. The one confounding variable that appeared to play a prominent role was alcohol intake. Among women who did not consume alcohol, the risk of breast cancer was not increased by current use of postmenopausal estrogen. By virtue of the large numbers in the Nurses' Health Study and the careful analyses by the investigators, reports from this study must be given great credibility. Although the earlier report from the Nurses' Health Study was comforting, the 10-year follow-up report is disturbing with its finding of an increased risk in current users. Because estrogen users may be examined more frequently, detection bias is a major concern. The investigators analyzed two factors that might be affected by detection bias (tumor size and lymph node metastasis at diagnosis) and found no difference between current users and never-users. It is noteworthy, however, that a higher percentage of current users had a mammogram during the previous year. It is also of note that current users had a lower odds ratio for death (0.82) compared with neverusers. The investigators argue that if the association between breast cancer and current use of replacement hormones was due to increased detection, past users should show evidence of protection. Overall, they believe that increased surveillance for breast cancer among current users of estrogen cannot, by itself, explain the apparent increased relative risk. They suggest that the lack of association between duration of estrogen use and increased risk of breast cancer among past users suggests that estrogen replacement therapy may promote or accelerate development of a breast cancer that was present during the early years of use. This conclusion of the Nurses' Health Study, of an increased relative risk in current users, is not definitive and not free of all confounding variables. Both the reduced odds ratio for death from breast cancer in current users and the absence of a statistically significant increased overall risk of fatal breast cancer among current users in the total cohort support the possibility of surveillance and detection bias. The size of the statistical risk is not outside the range of influence by this bias. A case-control study from Australia that attempted to control for secular trends in estrogen use, type of menopause, and duration of estrogen use concluded that there was no evidence for an association between estrogen use and the risk of breast cancer in postmenopausal women. 49 There is a very helpful study that specifically addressed the relationship between the use of estrogen and benign breast disease, s° This study is impressive in that it is based upon 10,366 consecutive breast biopsy specimens, with follow-up information on 4227 biopsy specimens in 3303 women (a mean duration of follow-up of 17 years). Analysis indicated that the use of estrogen was associated with a reduced risk of developing breast cancer. Most importantly, in patients with atypical hyperplasia on their biopsies, the use of estrogen lowered the risk of breast cancer. Although the protective effect may indicate surveillance bias, certainly this is strong evidence that estrogen use does not increase the risk of breast cancer in women with surgically proven benign breast disease. In September 1991, the Royal Society of Medicine sponsored a conference in London on hormone replacement therapy and breast cancer risk. Several case-control studies were updated, and preliminary data were reported from five new studies. A case-control study from Milan, Italy has been extended to 1929 cases and 1288 controls, with a relative risk for ever-users of estrogen of 1.2 (confidence interval 0.7-1.8). sl In a study of 1686 cases and 2077 controls in the eastern United States, the relative risk for current use was 1.1 (0.7-1.6) and for a duration of use of 15 or more years, 0.9 (0.4-1.9). 52 A study from
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Australia found no increased risk in current or past users.53 A study performed in Toronto found no evidence for an increased risk in either current or recent users or in users for up to 15 years. 54 A case-control study from Los Angeles found a slightly increased risk in users of unopposed estrogen, but the observation was not beyond the range of confounding biases. 55 Finally, a casecontrol study from Seattle was detailed, indicating that data from users of sequential estrogen and progestin will be available in late 1992. s6 Not a single one of the reports from the recent London meeting indicated an increased risk of breast cancer associated with unopposed estrogen of sufficient magnitude to be free of potential biases and a confidence interval tight enough to be statistically significant. Furthermore, these reports failed to support the conclusion of the Nurses' Health Study that current use is associated with an increased risk. Finally, data about the use of estrogen and progestin are beginning to emerge; the case-control study from Los Angeles could not detect a difference (either worse or better) comparing users of estrogen only with users of estrogen and progestin, ss
Meta-Analyses Examining Breast Cancer and Hormone Replacement Therapy Meta-analysis is an increasingly popular statistical method in which many studies are combined and undergo rigorous analysis. Simply put, the purpose of a meta-analysis is to gain the statistical power that is lacking in individual studies. An Australian meta-analysis of 23 studies of estrogen use and breast cancer concluded "unequivocally" that estrogen use did not alter the risk of breast cancer. 57 In the meta-analysis by Dupont and Page 58 in Nashville, the authors concluded that "considerable and consistent" evidence exists that a daily dose of 0.625 mg of conjugated estrogens taken for several years does not appreciably increase the risk of breast cancer. They found no evidence of an association between duration of treatment and the risk of breast cancer at this dosage. On the other hand, the bulk of the data suggest that a daily dose of at least 1.25 mg conjugated estrogens may increase the risk of breast cancer. This analysis failed to reveal an increased risk in patients with a history of benign breast disease. The latest meta-analysis is from the C D C . 59 This meta-analysis was conducted using what the authors called a "dose-response curve" for duration of use. The curve for each study analyzed was calculated by plotting breast cancer risk against duration of estrogen use. The combined dose-response slope represented the average change in risk associated with estrogen use over time. The analysis concluded that duration of estrogen use was associated with an increased risk of breast cancer, regardless of whether menopause was natural or surgical. No increase in risk was noted in the first 5 years of use, but after 15 years of use, the risk was increased by 30%. The effect was present irrespective of other risk factors, such as family history, parity, or history of benign breast disease. The effect of estrogen replacement on risk of breast cancer was enhanced in women with a positive family history of breast cancer. In contrast to the CDC report, the other two meta-analyses did not find an increased risk of breast cancer with increasing duration of estrogen use. The conclusion of the CDC meta-analysis may reflect the impact of high doses of estrogen. Both the Australian and Nashville meta-analyses indicated an increased risk with a daily dose of conjugated estrogens greater than 0.625 mg (or its equivalent). The Nashville and CDC analyses did not find an enhanced risk in women with a history of benign breast disease. In contrast to the CDC report, the Australian study found no link between positive family 68
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history and estrogen use. The Nashville investigators did not consider family history. The conclusions of the CDC meta-analysis are heavily influenced by a European study (the Uppsala cohort32) that had questionable statistical meaning. In addition, the overall conclusions reflect studies using relatively high doses of estrogen. This meta-analysis also contains a strong element of authorinduced selection bias of studies favoring increased risk. Cohort and casecontrol studies with a decreased relative risk were excluded. The results of a meta-analysis should not be accepted in a sacrosanct fashion. A meta-analysis can have the same problems encountered by individual epidemiologic studies. Selection bias is a major confounding variable. Where does that leave clinicians and patients? My impression is that the positive conclusions are strongly influenced by statistical limitations or by dose. The largest case-control study (from the CDC) and the largest cohort follow-up study (the Nurses' Health Study) failed to find a link between breast cancer and use of estrogen for up to 20 years. If estrogen use were associated with an increased risk of breast cancer, would there not be an impact on mortality? In the latest report from the Leisure World follow-up study in California, the risk of breast cancer mortality was 0.81. 6° This lower relative risk probably is influenced by an element of surveillance bias, but certainly there is no evidence that women using estrogen for a long time are dying of breast cancer at a greater rate. Doses of estrogen replacement known to protect against osteoporosis and cardiovascular disease (0.625 mg conjugated estrogens and 1.0 mg estradiol) are, at the present time, not known to be associated with any clear-cut increased risk of breast cancer. There is reason to be concerned over the use of higher doses. Patients who use higher doses of oral estrogen or who receive estrogen by injection or in pellet form might be at greater risk. For patients who are receiving estrogen by methods other than the standard oral route, monitoring blood estradiol levels is a useful precaution. The blood estradiol level should be in the range of 40-100 pg/mL; levels within this range are known to be associated with the benefits of estrogen replacement. Conclusion Clinicians and patients have rapidly turned to a new method of hormone replacement, a daily combination of estrogen and a progestin. Here is an excellent example of the utilization of a clinical method without the comfort of scientific support. The method is fast becoming popular in response to the patient's fear of an uncommon cancer and the need to overcome bleeding as a compliance problem, before studies have delineated the exact impact of a low dose of progestin on the estrogen protection against cardiovascular disease. The addition of a progestational agent to estrogen replacement therapy is now accepted as a standard part of the treatment program. The obvious reason for this combined estrogen-progestin approach is the need to prevent the increased risk of endometrial cancer associated with exposure to unopposed estrogen. Even though such endometrial cancer is not frequently encountered, and survival rates are excellent with early disease, the fear of this cancer is a major force in patient compliance and, therefore, the combined approach is warranted. In the future, attention will be directed to the combination program, estrogen and progestin, specifically to the impact of the progestational agent on the important health issues of the postmenopausal years. Breast cancer, of course, is a leading issue. Only two reports have claimed that the addition of a progestafional agent protects against breast cancer; the first, although it is the only randomized,
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placebo-controlled trial, was h a m p e r e d by small n u m b e r s , a n d the second was limited b y bias in t r e a t m e n t selection. 6~'62 The New England Journal of Medicine article from Uppsala is the first to suggest that the e s t r o g e n - p r o g e s t i n combination has an unfavorable impact on the risk of breast cancer but, as discussed above, this conclusion h a d little statistical power. Will sequential e s t r o g e n - p r o g e s t i n h a v e a different impact on the breast than the daily e x p o s u r e to c o m b i n e d e s t r o g e n - p r o g e s t i n ? Perhaps, in k e e p i n g with the h y p o t h e s i s stated by Key a n d Pike, 63 cyclic estrogen a n d p r o g e s t i n as in the normal m e n s t r u a l cycle are m o r e stressful for breast tissue. A daily exposure to a relatively stable e n v i r o n m e n t m a y p r o v e to be beneficial. O n l y time will tell. More studies and greater duration of use should p r o v i d e us with better a n s w e r s to m a n y of o u r questions. By virtue of the m a g n i t u d e of the postm e n o p a u s a l female population, these questions d e s e r v e continuing biologic and epidemiologic research from both the public health a n d individual points of view. Balancing the information available involving all of the health issues affected by h o r m o n e r e p l a c e m e n t therapy, a c o m b i n e d e s t r o g e n - p r o g e s t i n p r o g r a m in a p p r o p r i a t e doses offers significant benefits for p o s t m e n o p a u s a l women.
REFERENCES 1. Royal College of General Practitioners Oral Contraceptive Study. Further analyses of mortality in oral contraceptive users. Lancet 1981;i:541. 2. Vessey M, Baron J, Doll R, McPherson K,Yeates D. Oral contraceptives and breast cancer: Final report of an epidemiological study. Br J Cancer 1982;47:455. 3. Vessey M, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: Latest findings in a large cohort study. Br J Cancer 1989;59:613. 4. Ramcharan S, Pellegrin FA, Ray RM, Hsu J-P. A prospective study of the side effects of oral contraceptives. The Walnut Creek Contraceptive Drug Study. J Reprod Med 1980;25:360-6. 5. Romieu I, Willett WC, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, et al. Prospective study of oral contraceptive use and risk of breast cancer in women. J Natl Cancer Inst 1989;81:1313. 6. La Vecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, et al. Oral contraceptives and cancers of the breast and of the female genital tract: Interim results from a case-control study. Br J Cancer 1986;54:311. 7. Meirik O, Dami H, Christoffersen T, Lund E, Bergstrom R, Bergsjo P. Oral contraceptive use and breast cancer in young women. Lancet 1986;ii:650. 8. Kay CR, Hannaford PC. Breast cancer and the pill--further report from the Royal College of General Practitioners' oral contraceptive study. Br J Cancer 1988;58:675. 9. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New findings. Am J Epidemiol 1989;129:269. 10. United Kingdom National Case-Control Study Group. Oral contraceptive use and breast cancer risk in young women. Lancet 1989;i:973. 11. World Health Organization. Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and combined oral contraceptives: Results from a multinational study. Br J Cancer 1990;61:110. 12. McPherson K, Nell A, Vessey MP. Oral contraceptives and breast cancer. Lancet 1983;ii:414. 13. Hennekens CH, Speizer FE, Lipnik RJ, Rosner B, Bain C, Belanger C, et al. Casecontrol study of oral contraceptive use and breast cancer. J Natl Cancer Inst 1984;72:39. 14. Rosenberg L, Miller DR, Kaufman DW, Helmrich SP, Stolley PD, Schottenfeld D, et al. Breast cancer and oral contraceptive use. Am J Epidemiol 1984;119:167. 15. Stadel BV, Rubin GL, Webster LA, Schlesselman JJ, Wingo PA. Oral contraceptives and breast cancer in young women. Lancet 1985;ii:970.
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16. Paul C, Skegg DC, Spears GF, et al. Oral contraceptives and breast cancer: A national study. Br Med J 1986;293:723. 17. McPherson K, Vessey MP, Nell A, Doll R, Jones L, Roberts M. Early oral contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987;56:653. 18. Stadel BV, Lai SL. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988;38:287. 19. Stanford JL, Brinton LA, Hoover RN. Oral contraceptives and breast cancer: Results from an expanded case-control study. Br J Cancer 1989;60:375. 20. Schildkraut JM, Hulka BS, Wilkinson WE. Oral contraceptives and breast cancer: A case-control study with hospital and community controls. Obstet Gynecol 1990;76:395. 21. Lipnick RJ, Buring JE, Hennekens CH, Rosner B, Willett W, Bain C, et al. Oral contraceptives and breast cancer: A prospective cohort study. JAMA 1986;255:58. 22. Pike MC, Krailo MD, Henderson BE, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet 1983;ii:926. 23. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986;68:863. 24. Cancer and Steroid Hormone Study, Centers for Disease Control and National Institute for Child Health and Diseases. Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405. 25. Murray P, Schlesselman JJ, Stadel BV, Shenghan L. Oral contraceptives and breast cancer risk in women with a family history of breast cancer. Am J Obstet Gynecol 1989;73:977. 26. Schlesselman JJ, Stadel BV, Murray P, Shgenghan L. Breast cancer risk in relation to type of estrogen contained in oral contraceptives. Contraception 1987;36: 595. 27. Schlesselman JJ, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives: No evidence of a latent effect. JAMA 1988;259:1828. 28. Wingo PA, Lee NC, Ory HW, Beral V, Peterson HB, Rhodes P. Age-specific differences in the relationship between oral contraceptive use and breast cancer. Obstet Gynecol 1991;78:161. 29. Paul C, Skegg DCG, Spears GFS. Oral contraception and breast cancer in New Zealand. In: Mann RD, ed. Oral contraceptives and breast cancer. Park Ridge, New Jersey: Parthenon Publishing Group, 1990:85-98. 30. National Cancer Institute. Annual cancer statistics review, including cancer trends: 1950-1985. Bethesda, Maryland: National Institutes of Health, 1988. 31. Stadel BV, Schlesselman JJ. Oral contraceptive use and the risk of breast cancer in women with a "prior" history of benign breast disease. Am J Epidemiol 1986;123:373. 32. Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989;321:293. 33. Bergkvist L, Adami H-O, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221. 34. Bergkvist L, Tabar L, Adami H-O, Persson I, Bergstrom R. Mammographic parenchymal patterns in women receiving noncontraceptive estrogen treatment. Am J Epidemiol 1989;130:503. 35. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988;42:832. 36. Brinton LA, Hoover R, Fraumeni JF Jr. Menopausal oestrogens and breast cancer risk: An expanded case-control study. Br J Cancer 1986;54:825. 37. Hiatt RA, Bawol R, Friedman GD, Hoover R. Exogenous estrogen and breast cancer after bilateral oophorectomy. Cancer 1984;54:139. 38. Hoover R, Gray LA Sr, Cole P, MacMahon B. Menopausal estrogens and breast cancer. N Engl J Med 1976;295:401. 39. Hoover R, Glass A, Finkle WE, et al. Conjugated estrogens and breast cancer risk in women. J Natl Cancer Inst 1981;67:815.
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40. Hulka BS, Chambless LE, Deubner DC, Wilkinson WE. Breast cancer and estrogen replacement therapy. Am J Obstet Gynecol 1982;143:638. 41. Jick H, Walker AM, Watkins RN, et al. Replacement estrogens and breast cancer. Am J Epidemiol 1980;112:586. 42. Kaufman DW, Miller DR, Rosenberg L, Helmrich SP, Stolly P, Schottenfeld D. Noncontraceptive estrogen use and the risk of breast cancer. JAMA 1984;252:63. 43. Kelsey JL, Fischer DB, Holford TR, et al. Exogenous estrogens and other factors in the epidemiology of breast cancer. J Natl Cancer Inst 1981;67:327. 44. Lawson DH, Jick H, Hunter JR, Madsen S. Exogenous estrogens and breast cancer. Am J Epidemiol 1981;114:710. 45. Ross RK, Paganini-Hill A, Gerkins VR, et al. A case-control study of menopausal estrogen therapy and breast cancer. JAMA 1980;243:1635. 46. Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. JAMA 1987;257:209. 47. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 1990;264:2648. 48. Buring JE, Hennekens CH, Lipnick RJ, Willett W, Stampfer MJ, Rosner B, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in U.S. women. Am J Epidemiol 1987;125:939. 49. Rohan TE, McMichael AJ. Non-contraceptive exogenous oestrogen therapy and breast cancer. Med J Aust 1988;148:217. 50. Dupont WD, Page DL, Rogers LW, Parl FF. Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer 1989;63:948. 51. La Vecchia C. Non-contraceptive oestrogens and breast cancer: Update of an Italian case-control study. The Royal Society of Medicine, London, September 24-26, 1991. 52. Kaufman DW, Palmer JR, Rosenberg L, Shapiro S. Oestrogen replacement therapy and breast cancer: New results from the Slone Epidemiology Unit's Case Control Surveillance Study. The Royal Society of Medicine, London, September 24-26, 1991. 53. Rohan T. Hormone replacement therapy and risk of breast cancer: A populationbased case-control study in Australia. The Royal Society of Medicine, London, September 24-26, 1991. 54. Rosenberg I, Palmer JR, Shapiro S. Oestrogen replacement therapy and breast cancer: Results from the Slone Epidemiology Unit's Toronto Breast Cancer Study. The Royal Society of Medicine, London, September 24-26, 1991. 55. Ross RK, Bernstein L. Why can't we prove that HRT causes breast cancer? Methodologic and biologic challenges. The Royal Society of Medicine, London, September 24-26, 1991. 56. Weiss NS. Case-control studies of exogenous sex hormones in relation to breast cancer in women conducted in western Washington. The Royal Society of Medicine, London, September 24-26, 1991. 57. Armstrong BK. Oestrogen therapy after the menopause--boon or bane? Med J Aust 1988;148:213. 58. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991;151:67. 59. Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders D, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991;265:1985. 60. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75. 61. Gambrell RD Jr, Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol 1983;62:435. 62. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy: II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979;54:74. 63. Key TJA, Pike MC. The role of oestrogens and progestogens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 1988;24:29.
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DISCUSSION Assessing the impact of estrogen use on the risk of breast cancer is one of the more confusing issues in practice today. Many questions cannot be answered until more data emerge. Frustratingly, the few long-term studies that are now available for oral contraceptives are based on higher estrogen dosages than today's low-dose formulations. It will be another 5-10 years before conclusive data showing the effect of low-dose contraceptives on breast cancer risk are available, Dr. Speroff predicted. The studies on hormone replacement therapy that are emerging, such as the Uppsala, Sweden study, do produce waves of concern. These data must be interpreted carefully for variables that can confound the results. Dr. Judith LaRosa pointed out the hysteria being generated by lay interpretations of study results and averred that the review of studies presented today by Dr. Speroff was something from which countless audiences could benefit. Among the clinical issues raised was Dr. Dunn's question about whether women at high risk for ovarian cancer through family history ought to be prescribed low-dose oral contraceptives as a prophylaxis. Low-dose contraceptives have been shown to have a protective effect against ovarian cancer and endometrial cancer. Dr. Speroff replied that certainly when such women are in the position of needing contraception, there are enough data to recommend oral contraception emphatically. Their prophylactic use would be comparable to prescribing the pill to prevent endometriosis in patients with tubal ligations, which is frequently done. For the rare patient with a strong family history of ovarian cancer who no longer needs contraception, Dr. Speroff recommended a more drastic preventive measure---prophylactic oophorectomy. Dr. John LaRosa offered his impression that, in the aggregate, the data tend to favor a slightly increased risk of breast cancer with estrogen use. Although the difference might be so small as to not be clinically significant, and might not affect his treatment decisions with individual patients, it nonetheless appears to be there. He inquired about the rationale behind the current estrogen dose given in long-term hormone replacement therapy and asked why a lower dosage hadn't been considered. Dr. Speroff replied that there is a point at which estrogen no longer protects against bone loss. He added that the same dose may not be appropriate for everyone, and said the Food and Drug Administration is now requiring that companies seeking premarket approval for their hormone replacement product specify the lowest effective dose. The bulk of the discussion revolved around process, ie, how can policymakers, medical organizations, and individual providers behave in a responsible manner concerning these issues? Mr. Tennenbaum observed that the public seems unaware of the amount of internal scrutiny and debate going on within the medical community. He asked what the individual practitioner should be expected to do in the light of so much divided opinion, and wondered what guidance could be provided by medical specialty societies and other groups. Dr. Speroff replied that the medical societies with which he is involved-ACOG and the American Fertility Society--take that charge very seriously, and have established guidelines for practice and incorporated these topics into continuing medical education programs. Dr. Schwarz illuminated the process of consensus-building as it occurs within specialty societies. The most critical period tends to be before there are sufficient data for such groups to comfortably endorse a concept, he said--that's when mischief occurs. He said ACOG's committees tend to be conservative, that although they try to respond as quickly as possible to convincing data, they also exercise restraint against WHI Vol. 2, No. 2 S u m m e r 1992
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reaching conclusions prematurely. Meanwhile, television and the newspapers begin spreading information, and that creates pressure on such groups to respond before they're ready. Dr. Ruth Merkatz added that specialty groups have an obligation not only to inform their own members, but also to inform the public. Much of what the public learns today stems from television and lacks the perspective of professional sources who perhaps understand it best. Dr. Speroff acknowledged a "pet p e e v e ' - - t h a t the role of nurses in this area is often neglected. Nurses play a critical role in patient interactions; in this case of hormone replacement therapy, they are in a powerful position to influence patients' understanding. There was discussion about the advance release to the press of clinical data as currently practiced by some medical journals. Dr. Ravnikar pointed out that even the medical journals fall prey to wanting to get into the limelight once in a while. Dr. Speroff voiced support for a proposed Jacobs Institute conference that would focus on media reporting of women's health issues and address many of the problems raised today (ie, how to read studies properly, avoiding conclusions based on premature data, etc). Dr. John LaRosa returned to the overall issue of how broad the public message about oral contraception and hormone replacement therapy ought to be at this point. He drew a distinction between the level of certainty about these topics and that behind the issue of lowering cholesterol to prevent coronary artery disease, for example. Data for the latter are well established, and the federal government--which in his estimation is appropriately slow in acting on these matters---has endorsed a standard of care contained within the large-scale National Cholesterol Education Program. In contrast, the immaturity of data involving hormone replacement therapy would make it inappropriate to react with broadly disseminated recommendations. Dr. Speroff agreed and said for that reason he supports the efforts within the Office of Women's Health at the National Institutes of Health to design a clinical trial of hormone replacement therapy that would provide the scientific basis for developing a standard of practice. He would not await the issuance of such data in treating his own patients because, in his judgment, the evidence in favor of hormone replacement therapy already is convincing.
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ral contraception and hormone replacement therapy can, in my view, be legitimately regarded as components of preventive health care for women. An important obstacle to achieving the benefits of these two health care programs is the maintenance of good compliance. Despite the fact that oral contraception is highly effective, hundreds of thousands of unintended pregnancies occur each year in the United States because of poor compliance. It is also well recognized that only about onethird of postmenopausal women continue their regimen of hormone replacement beyond 1 year's time. Compliance is an area in which personal behavior, biology, and pharmacology come together. There are three major factors that affect compliance: fears and concerns regarding serious side effects, the experience of minor side effects, and nonmedical issues such as inadequate instructions. The fear of cancer, especially breast cancer, plays an important role in noncompliance. Indeed, the actual fear of the possibility of cancer is a more important patient response and consideration than the precise knowledge regarding the presence or absence of an association with any given treatment. The clinician's ability to deal with this fear, however, requires a good understanding of available and current data. This is an era of informed choice by the patient. Patients deserve to know the facts and need help in dealing with the state of the art and the uncertainty. But there is no doubt that patients are influenced in their choices by their clinician's advice and attitude. Although the role of a clinician is to provide the education necessary for the patient to make proper choices, one should not lose sight of the powerful influence exerted by the clinician in the choices ultimately made. Because of the above considerations, it is very important to assess the state of knowledge regarding the risk of breast cancer with oral contraception and hormone replacement therapy. This is the information the clinician needs to bring to the individual patient-clinician encounter.
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ORAL C O N T R A C E P T I O N A N D THE RISK OF BREAST C A N C E R Until the mid-1980s, there was a consistent absence of any epidemiologic data linking oral contraception with an increased risk of breast cancer. Over the last several years, several investigators reported a shift from negative results to positive results. It was suggested that this shift was due to a change in usage of oral contraception, from use in the 1960s by older w o m e n to space out children, to use in the 1980s by y o u n g w o m e n to delay an initial pregnancy. Because a full-term p r e g n a n c y early in life protects against breast cancer, it is an important possibility that participants in these studies are, for the first time, fulfilling specific conditions that might predispose t h e m to an increased risk of breast cancer. It is possible that this is the reason w h y the major cohort studies (the Royal College of General Practitioners Study, the Oxford Family Planning Association Study, the Walnut Creek Study, and the Nurses' Health Study) that recruited participants in the 1960s and 1970s have failed to find any significant differences in breast cancer rates b e t w e e n users and nonusers of oral contraception. 1-5 Over the last decade, therefore, case-control studies have focused on the use of oral contraception early in life, for long durations, and to delay a first, full-term pregnancy. Because the cohort of w o m e n w h o have used oral contraception in this fashion is just n o w beginning to reach the ages of postmenopausal breast cancer, the studies have had to examine the risk of breast cancer diagnosed before age 45 (which is only 13% of all breast cancers). Some of these recent case-control studies have indicated an overall increased relative risk of early, p r e m e n o p a u s a l breast cancer, 6-11 whereas others indicated no increase in overall risk. ~2-21 Examining use before a first full-term pregnancy does not yield consistent results. Some studies indicate an increased risk for breast cancer, 22 but most do n o t . 6"1°A1"16'18-2°'23 These inconsistent conclusions may reflect epidemiologic difficulties. For example, in the Oxford Family Planning Association study, the relative risk for use before a first full-term pregnancy was 2.59; however, only 2% of their patients u s e d oral contraception before a first full-term pregnancy.17 For use before age 25, the majority of studies, but not all, indicated no increased risk of breast cancer. The most impressive finding indicates a link in most s t u d i e s , 7"9"1°'17AS"z2 but not all, 19'2° of early breast cancer before age 40 in w o m e n w h o used oral contraception for long durations of time. The Centers for Disease Control (CDC) Cancer and Sex H o r m o n e (CASH) study is the largest case-control s t u d y on the s u b j e c t . 24-26 No overall increased risk of breast cancer was f o u n d in w o m e n first using oral contraceptives before the age of 20 with a duration of use greater than 4 years, or before the age of 25 with a duration of use greater than 6 years, or with greater than 4 years' use before a first pregnancy. In addition, no overall increased risk of breast cancer was found a m o n g any subgroups of users including w o m e n with benign breast disease or a family history of breast cancer. There was no increased risk associated with any specific type of oral contraceptive or progestin-only pills, or the use of two or more types. In addition, there was no increased risk associated with any specific progestin or estrogen c o m p o n e n t and, most importantly, it was d e m o n s t r a t e d that long-term use (15 or more years) was not associated with an increased risk of breast cancer. Thus far, the CDC study has f o u n d no evidence for a latent effect on breast cancer risk through age 54. 27 The CDC has recently reexamined their data to determine w h e t h e r oral contraceptive use had different effects on the risk of breast cancer diagnosed at different ages. 28 This analysis indicated that oral contraceptive use slightly increased the risk of breast cancer diagnosed u n d e r the age of 35
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and had no effect on women diagnosed from age 35-44; in women diagnosed from age 45-54, oral contraceptive use appeared to decrease the risk of breast cancer. However, these estimates were of borderline statistical significance. The protection that oral contraceptive use appeared to provide to older women is a more convincing argument because it was supported by several dose-response relationships (age with first use and time since first and last use). The elevated risk among the women with early breast cancer is a more tenuous conclusion, not strengthened by supporting doseresponse patterns. The crucial question is: As studies gain more statistical power, will they confirm a slightly increased risk for premenopausal breast cancer or will the present suggestion of an increased risk disappear? For example, an early report from New Zealand indicated an increased relative risk for premenopausal breast cancer and, as the study continues, this relative risk is moving closer and closer to 1.0. 29 Further comfort can be derived from the United States national cancer surveillance data. 3° The increase in breast cancer in American women is in older women, those who did not have the opportunity to use oral contraception. In women under 56 years of age, there has been no change in the age-specific breast cancer rates from 1950-1985.
Conclusion
The following conclusions can be drawn from the currently available epidemiologic data: 1. Long-term use of oral contraception during the reproductive years is not associated with a significant increase in the risk of breast cancer after age 45. Indeed, there is the possibility, as suggested by the recent CDC report, that exposure to early contraception confers some degree of protection against postmenopausal breast cancer. 2. There has been consistent failure to demonstrate an increased risk of breast cancer with oral contraceptive use in women with positive family histories of breast cancer or in women with proven benign breast disease. 25"31 3. There is the possibility that a young subgroup of women who use oral contraception early and for a long time (4 years or more) has a slightly increased risk of breast cancer before the age of 45, a relative risk of less than 1.5. Keep in mind that this possibility is derived from studies of older, higherdose oral contraception. There are at least two reasons that make continuing studies on this issue important. First is the aging of the cohort of users and the need to both increase the statistical power of the current studies and to determine the emerging risk as these women age. Second, the possibility of greater safety with lower dosage must be documented. When adding up the benefits of oral contraception, the possible slight increase in risk of breast cancer is far outweighed by positive effects on our public health. But the impact on public health is of little concern during the private clinician-patient interchange in the office. Here personal risk receives highest priority; fear of cancer is a motivating force, and compliance with effective contraception requires accurate information. I believe it is appropriate to state that there is no definitive evidence demonstrating a link between breast cancer and oral contraception. On the other hand, patients deserve to know about our concern and about the findings regarding long duration of use and the possible increased risk of early, premenopausal breast cancer. As long as the inconsistencies exist in the epidemiologic evidence, the clinician is justified in being optimistic, stating that risk is possible but has not been proven. WHI Vol. 2, No. 2 Summer 1992
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H O R M O N E REPLACEMENT THERAPY A N D THE RISK OF BREAST CANCER A recent study from Uppsala, Sweden concluded that postmenopausal estrogen use was associated with a slight increase in the risk of breast cancer (relative risk 1.1), and that there was a relationship with duration of use; the relative risk reached 1.7 after 9 years. 32 This increased risk was associated only with the use of estradiol (in a dose approximately double the current standard in the United States). The authors indicated that this investigation was a case-cohort type of epidemiologic study, prospective in the nature of its follow-up. The impression, strongly given, was that the cohort was large, consisting of 23,244 women. Actually the cohort consisted of the 653 w om en who answered a questionnaire sent to 1 in 30 of the 23,244 women. One should note immediately that 11% did not return the questionnaire, introducing the question of selection bias. The results in this subgroup were extrapolated to the large group of women. The authors correctly indicated that there was a trend toward increasing relative risk with duration of use (in other words, it was not statistically significant). The confidence intervals included 1.0 and, by definition, this is not statistically significant. The indication of increased risk with sequential estrogen-progestin was based on only ten wom en with breast cancer, and the confidence interval was impressively wide: 0.9-22.4. A further indication that bias may have influenced the results can be found in another publication by the same Uppsala group utilizing the same cohort. They concluded that women using estrogen who develop breast cancer have a more favorable course with a higher survival rate. 33 In that report, selection bias and surveillance bias were very possible. They further reported, in yet another publication, that estrogen users more commonly had a high risk pattern on mammography, another possible confounding variable. 34 A case-control study from Denmark that also utilized questionnaires to obtain information from both the cases and controls concluded that there was a slightly increased risk of breast cancer associated with sequential estrogen and progestin therapy. 3s This study contains limitations similar to the Uppsala study (small numbers of cases and statistically nonsignificant conclusions). Earlier studies indicated higher risks in special subcategories such as women with benign breast disease, long duration of use, or natural versus surgical menopause. 36-4s These studies suffered several statistical problems: lack of appropriate controls, differences in doses, and small numbers. The CASH study of the CDC is a large, population-based, case-control study from eight geographic locations. The CASH study has not detected an overall increased risk of breast cancer with postmenopausal estrogen use and has detected no relationship with duration of use up to 20 years or longer. 46 There were positive findings in certain subgroups, most notably in w om en with menopause because of bilateral oophorectomy. However, the confidence intervals in these subgroup analyses include 1.0 and therefore the conclusions did not reach statistical significance. The latest report from the Nurses' Health Study represents 10 years of follow-up (1976-1986). 47 During that period, 722 cases of breast cancer were identified among more than 20,000 women. The analysis revealed that w om en who had used replacement estrogen in the past (even for 10 or more years) were not at increased risk of breast cancer. However, the relative risk for current users was 1.36 (confidence interval 1.11-1.67). An earlier report from this cohort (based on only 4 years of follow-up) was totally negative in terms of an association between current use of estrogen replacement and risk of breast cancer. 48 The investigators believe their current finding is within the confidence interval of the earlier analysis. Compared with never-users, cur66
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rent users were slightly more likely to have certain risk factors (history of benign breast disease, nulliparity, use of alcohol). However, adjustment for several of these risk factors only minimally reduced the relative risk for current use. The one confounding variable that appeared to play a prominent role was alcohol intake. Among women who did not consume alcohol, the risk of breast cancer was not increased by current use of postmenopausal estrogen. By virtue of the large numbers in the Nurses' Health Study and the careful analyses by the investigators, reports from this study must be given great credibility. Although the earlier report from the Nurses' Health Study was comforting, the 10-year follow-up report is disturbing with its finding of an increased risk in current users. Because estrogen users may be examined more frequently, detection bias is a major concern. The investigators analyzed two factors that might be affected by detection bias (tumor size and lymph node metastasis at diagnosis) and found no difference between current users and never-users. It is noteworthy, however, that a higher percentage of current users had a mammogram during the previous year. It is also of note that current users had a lower odds ratio for death (0.82) compared with neverusers. The investigators argue that if the association between breast cancer and current use of replacement hormones was due to increased detection, past users should show evidence of protection. Overall, they believe that increased surveillance for breast cancer among current users of estrogen cannot, by itself, explain the apparent increased relative risk. They suggest that the lack of association between duration of estrogen use and increased risk of breast cancer among past users suggests that estrogen replacement therapy may promote or accelerate development of a breast cancer that was present during the early years of use. This conclusion of the Nurses' Health Study, of an increased relative risk in current users, is not definitive and not free of all confounding variables. Both the reduced odds ratio for death from breast cancer in current users and the absence of a statistically significant increased overall risk of fatal breast cancer among current users in the total cohort support the possibility of surveillance and detection bias. The size of the statistical risk is not outside the range of influence by this bias. A case-control study from Australia that attempted to control for secular trends in estrogen use, type of menopause, and duration of estrogen use concluded that there was no evidence for an association between estrogen use and the risk of breast cancer in postmenopausal women. 49 There is a very helpful study that specifically addressed the relationship between the use of estrogen and benign breast disease, s° This study is impressive in that it is based upon 10,366 consecutive breast biopsy specimens, with follow-up information on 4227 biopsy specimens in 3303 women (a mean duration of follow-up of 17 years). Analysis indicated that the use of estrogen was associated with a reduced risk of developing breast cancer. Most importantly, in patients with atypical hyperplasia on their biopsies, the use of estrogen lowered the risk of breast cancer. Although the protective effect may indicate surveillance bias, certainly this is strong evidence that estrogen use does not increase the risk of breast cancer in women with surgically proven benign breast disease. In September 1991, the Royal Society of Medicine sponsored a conference in London on hormone replacement therapy and breast cancer risk. Several case-control studies were updated, and preliminary data were reported from five new studies. A case-control study from Milan, Italy has been extended to 1929 cases and 1288 controls, with a relative risk for ever-users of estrogen of 1.2 (confidence interval 0.7-1.8). sl In a study of 1686 cases and 2077 controls in the eastern United States, the relative risk for current use was 1.1 (0.7-1.6) and for a duration of use of 15 or more years, 0.9 (0.4-1.9). 52 A study from
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Australia found no increased risk in current or past users.53 A study performed in Toronto found no evidence for an increased risk in either current or recent users or in users for up to 15 years. 54 A case-control study from Los Angeles found a slightly increased risk in users of unopposed estrogen, but the observation was not beyond the range of confounding biases. 55 Finally, a casecontrol study from Seattle was detailed, indicating that data from users of sequential estrogen and progestin will be available in late 1992. s6 Not a single one of the reports from the recent London meeting indicated an increased risk of breast cancer associated with unopposed estrogen of sufficient magnitude to be free of potential biases and a confidence interval tight enough to be statistically significant. Furthermore, these reports failed to support the conclusion of the Nurses' Health Study that current use is associated with an increased risk. Finally, data about the use of estrogen and progestin are beginning to emerge; the case-control study from Los Angeles could not detect a difference (either worse or better) comparing users of estrogen only with users of estrogen and progestin, ss
Meta-Analyses Examining Breast Cancer and Hormone Replacement Therapy Meta-analysis is an increasingly popular statistical method in which many studies are combined and undergo rigorous analysis. Simply put, the purpose of a meta-analysis is to gain the statistical power that is lacking in individual studies. An Australian meta-analysis of 23 studies of estrogen use and breast cancer concluded "unequivocally" that estrogen use did not alter the risk of breast cancer. 57 In the meta-analysis by Dupont and Page 58 in Nashville, the authors concluded that "considerable and consistent" evidence exists that a daily dose of 0.625 mg of conjugated estrogens taken for several years does not appreciably increase the risk of breast cancer. They found no evidence of an association between duration of treatment and the risk of breast cancer at this dosage. On the other hand, the bulk of the data suggest that a daily dose of at least 1.25 mg conjugated estrogens may increase the risk of breast cancer. This analysis failed to reveal an increased risk in patients with a history of benign breast disease. The latest meta-analysis is from the C D C . 59 This meta-analysis was conducted using what the authors called a "dose-response curve" for duration of use. The curve for each study analyzed was calculated by plotting breast cancer risk against duration of estrogen use. The combined dose-response slope represented the average change in risk associated with estrogen use over time. The analysis concluded that duration of estrogen use was associated with an increased risk of breast cancer, regardless of whether menopause was natural or surgical. No increase in risk was noted in the first 5 years of use, but after 15 years of use, the risk was increased by 30%. The effect was present irrespective of other risk factors, such as family history, parity, or history of benign breast disease. The effect of estrogen replacement on risk of breast cancer was enhanced in women with a positive family history of breast cancer. In contrast to the CDC report, the other two meta-analyses did not find an increased risk of breast cancer with increasing duration of estrogen use. The conclusion of the CDC meta-analysis may reflect the impact of high doses of estrogen. Both the Australian and Nashville meta-analyses indicated an increased risk with a daily dose of conjugated estrogens greater than 0.625 mg (or its equivalent). The Nashville and CDC analyses did not find an enhanced risk in women with a history of benign breast disease. In contrast to the CDC report, the Australian study found no link between positive family 68
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history and estrogen use. The Nashville investigators did not consider family history. The conclusions of the CDC meta-analysis are heavily influenced by a European study (the Uppsala cohort32) that had questionable statistical meaning. In addition, the overall conclusions reflect studies using relatively high doses of estrogen. This meta-analysis also contains a strong element of authorinduced selection bias of studies favoring increased risk. Cohort and casecontrol studies with a decreased relative risk were excluded. The results of a meta-analysis should not be accepted in a sacrosanct fashion. A meta-analysis can have the same problems encountered by individual epidemiologic studies. Selection bias is a major confounding variable. Where does that leave clinicians and patients? My impression is that the positive conclusions are strongly influenced by statistical limitations or by dose. The largest case-control study (from the CDC) and the largest cohort follow-up study (the Nurses' Health Study) failed to find a link between breast cancer and use of estrogen for up to 20 years. If estrogen use were associated with an increased risk of breast cancer, would there not be an impact on mortality? In the latest report from the Leisure World follow-up study in California, the risk of breast cancer mortality was 0.81. 6° This lower relative risk probably is influenced by an element of surveillance bias, but certainly there is no evidence that women using estrogen for a long time are dying of breast cancer at a greater rate. Doses of estrogen replacement known to protect against osteoporosis and cardiovascular disease (0.625 mg conjugated estrogens and 1.0 mg estradiol) are, at the present time, not known to be associated with any clear-cut increased risk of breast cancer. There is reason to be concerned over the use of higher doses. Patients who use higher doses of oral estrogen or who receive estrogen by injection or in pellet form might be at greater risk. For patients who are receiving estrogen by methods other than the standard oral route, monitoring blood estradiol levels is a useful precaution. The blood estradiol level should be in the range of 40-100 pg/mL; levels within this range are known to be associated with the benefits of estrogen replacement. Conclusion Clinicians and patients have rapidly turned to a new method of hormone replacement, a daily combination of estrogen and a progestin. Here is an excellent example of the utilization of a clinical method without the comfort of scientific support. The method is fast becoming popular in response to the patient's fear of an uncommon cancer and the need to overcome bleeding as a compliance problem, before studies have delineated the exact impact of a low dose of progestin on the estrogen protection against cardiovascular disease. The addition of a progestational agent to estrogen replacement therapy is now accepted as a standard part of the treatment program. The obvious reason for this combined estrogen-progestin approach is the need to prevent the increased risk of endometrial cancer associated with exposure to unopposed estrogen. Even though such endometrial cancer is not frequently encountered, and survival rates are excellent with early disease, the fear of this cancer is a major force in patient compliance and, therefore, the combined approach is warranted. In the future, attention will be directed to the combination program, estrogen and progestin, specifically to the impact of the progestational agent on the important health issues of the postmenopausal years. Breast cancer, of course, is a leading issue. Only two reports have claimed that the addition of a progestafional agent protects against breast cancer; the first, although it is the only randomized,
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placebo-controlled trial, was h a m p e r e d by small n u m b e r s , a n d the second was limited b y bias in t r e a t m e n t selection. 6~'62 The New England Journal of Medicine article from Uppsala is the first to suggest that the e s t r o g e n - p r o g e s t i n combination has an unfavorable impact on the risk of breast cancer but, as discussed above, this conclusion h a d little statistical power. Will sequential e s t r o g e n - p r o g e s t i n h a v e a different impact on the breast than the daily e x p o s u r e to c o m b i n e d e s t r o g e n - p r o g e s t i n ? Perhaps, in k e e p i n g with the h y p o t h e s i s stated by Key a n d Pike, 63 cyclic estrogen a n d p r o g e s t i n as in the normal m e n s t r u a l cycle are m o r e stressful for breast tissue. A daily exposure to a relatively stable e n v i r o n m e n t m a y p r o v e to be beneficial. O n l y time will tell. More studies and greater duration of use should p r o v i d e us with better a n s w e r s to m a n y of o u r questions. By virtue of the m a g n i t u d e of the postm e n o p a u s a l female population, these questions d e s e r v e continuing biologic and epidemiologic research from both the public health a n d individual points of view. Balancing the information available involving all of the health issues affected by h o r m o n e r e p l a c e m e n t therapy, a c o m b i n e d e s t r o g e n - p r o g e s t i n p r o g r a m in a p p r o p r i a t e doses offers significant benefits for p o s t m e n o p a u s a l women.
REFERENCES 1. Royal College of General Practitioners Oral Contraceptive Study. Further analyses of mortality in oral contraceptive users. Lancet 1981;i:541. 2. Vessey M, Baron J, Doll R, McPherson K,Yeates D. Oral contraceptives and breast cancer: Final report of an epidemiological study. Br J Cancer 1982;47:455. 3. Vessey M, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: Latest findings in a large cohort study. Br J Cancer 1989;59:613. 4. Ramcharan S, Pellegrin FA, Ray RM, Hsu J-P. A prospective study of the side effects of oral contraceptives. The Walnut Creek Contraceptive Drug Study. J Reprod Med 1980;25:360-6. 5. Romieu I, Willett WC, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, et al. Prospective study of oral contraceptive use and risk of breast cancer in women. J Natl Cancer Inst 1989;81:1313. 6. La Vecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, et al. Oral contraceptives and cancers of the breast and of the female genital tract: Interim results from a case-control study. Br J Cancer 1986;54:311. 7. Meirik O, Dami H, Christoffersen T, Lund E, Bergstrom R, Bergsjo P. Oral contraceptive use and breast cancer in young women. Lancet 1986;ii:650. 8. Kay CR, Hannaford PC. Breast cancer and the pill--further report from the Royal College of General Practitioners' oral contraceptive study. Br J Cancer 1988;58:675. 9. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New findings. Am J Epidemiol 1989;129:269. 10. United Kingdom National Case-Control Study Group. Oral contraceptive use and breast cancer risk in young women. Lancet 1989;i:973. 11. World Health Organization. Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and combined oral contraceptives: Results from a multinational study. Br J Cancer 1990;61:110. 12. McPherson K, Nell A, Vessey MP. Oral contraceptives and breast cancer. Lancet 1983;ii:414. 13. Hennekens CH, Speizer FE, Lipnik RJ, Rosner B, Bain C, Belanger C, et al. Casecontrol study of oral contraceptive use and breast cancer. J Natl Cancer Inst 1984;72:39. 14. Rosenberg L, Miller DR, Kaufman DW, Helmrich SP, Stolley PD, Schottenfeld D, et al. Breast cancer and oral contraceptive use. Am J Epidemiol 1984;119:167. 15. Stadel BV, Rubin GL, Webster LA, Schlesselman JJ, Wingo PA. Oral contraceptives and breast cancer in young women. Lancet 1985;ii:970.
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16. Paul C, Skegg DC, Spears GF, et al. Oral contraceptives and breast cancer: A national study. Br Med J 1986;293:723. 17. McPherson K, Vessey MP, Nell A, Doll R, Jones L, Roberts M. Early oral contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987;56:653. 18. Stadel BV, Lai SL. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988;38:287. 19. Stanford JL, Brinton LA, Hoover RN. Oral contraceptives and breast cancer: Results from an expanded case-control study. Br J Cancer 1989;60:375. 20. Schildkraut JM, Hulka BS, Wilkinson WE. Oral contraceptives and breast cancer: A case-control study with hospital and community controls. Obstet Gynecol 1990;76:395. 21. Lipnick RJ, Buring JE, Hennekens CH, Rosner B, Willett W, Bain C, et al. Oral contraceptives and breast cancer: A prospective cohort study. JAMA 1986;255:58. 22. Pike MC, Krailo MD, Henderson BE, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet 1983;ii:926. 23. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986;68:863. 24. Cancer and Steroid Hormone Study, Centers for Disease Control and National Institute for Child Health and Diseases. Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405. 25. Murray P, Schlesselman JJ, Stadel BV, Shenghan L. Oral contraceptives and breast cancer risk in women with a family history of breast cancer. Am J Obstet Gynecol 1989;73:977. 26. Schlesselman JJ, Stadel BV, Murray P, Shgenghan L. Breast cancer risk in relation to type of estrogen contained in oral contraceptives. Contraception 1987;36: 595. 27. Schlesselman JJ, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives: No evidence of a latent effect. JAMA 1988;259:1828. 28. Wingo PA, Lee NC, Ory HW, Beral V, Peterson HB, Rhodes P. Age-specific differences in the relationship between oral contraceptive use and breast cancer. Obstet Gynecol 1991;78:161. 29. Paul C, Skegg DCG, Spears GFS. Oral contraception and breast cancer in New Zealand. In: Mann RD, ed. Oral contraceptives and breast cancer. Park Ridge, New Jersey: Parthenon Publishing Group, 1990:85-98. 30. National Cancer Institute. Annual cancer statistics review, including cancer trends: 1950-1985. Bethesda, Maryland: National Institutes of Health, 1988. 31. Stadel BV, Schlesselman JJ. Oral contraceptive use and the risk of breast cancer in women with a "prior" history of benign breast disease. Am J Epidemiol 1986;123:373. 32. Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989;321:293. 33. Bergkvist L, Adami H-O, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221. 34. Bergkvist L, Tabar L, Adami H-O, Persson I, Bergstrom R. Mammographic parenchymal patterns in women receiving noncontraceptive estrogen treatment. Am J Epidemiol 1989;130:503. 35. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988;42:832. 36. Brinton LA, Hoover R, Fraumeni JF Jr. Menopausal oestrogens and breast cancer risk: An expanded case-control study. Br J Cancer 1986;54:825. 37. Hiatt RA, Bawol R, Friedman GD, Hoover R. Exogenous estrogen and breast cancer after bilateral oophorectomy. Cancer 1984;54:139. 38. Hoover R, Gray LA Sr, Cole P, MacMahon B. Menopausal estrogens and breast cancer. N Engl J Med 1976;295:401. 39. Hoover R, Glass A, Finkle WE, et al. Conjugated estrogens and breast cancer risk in women. J Natl Cancer Inst 1981;67:815.
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40. Hulka BS, Chambless LE, Deubner DC, Wilkinson WE. Breast cancer and estrogen replacement therapy. Am J Obstet Gynecol 1982;143:638. 41. Jick H, Walker AM, Watkins RN, et al. Replacement estrogens and breast cancer. Am J Epidemiol 1980;112:586. 42. Kaufman DW, Miller DR, Rosenberg L, Helmrich SP, Stolly P, Schottenfeld D. Noncontraceptive estrogen use and the risk of breast cancer. JAMA 1984;252:63. 43. Kelsey JL, Fischer DB, Holford TR, et al. Exogenous estrogens and other factors in the epidemiology of breast cancer. J Natl Cancer Inst 1981;67:327. 44. Lawson DH, Jick H, Hunter JR, Madsen S. Exogenous estrogens and breast cancer. Am J Epidemiol 1981;114:710. 45. Ross RK, Paganini-Hill A, Gerkins VR, et al. A case-control study of menopausal estrogen therapy and breast cancer. JAMA 1980;243:1635. 46. Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. JAMA 1987;257:209. 47. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 1990;264:2648. 48. Buring JE, Hennekens CH, Lipnick RJ, Willett W, Stampfer MJ, Rosner B, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in U.S. women. Am J Epidemiol 1987;125:939. 49. Rohan TE, McMichael AJ. Non-contraceptive exogenous oestrogen therapy and breast cancer. Med J Aust 1988;148:217. 50. Dupont WD, Page DL, Rogers LW, Parl FF. Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer 1989;63:948. 51. La Vecchia C. Non-contraceptive oestrogens and breast cancer: Update of an Italian case-control study. The Royal Society of Medicine, London, September 24-26, 1991. 52. Kaufman DW, Palmer JR, Rosenberg L, Shapiro S. Oestrogen replacement therapy and breast cancer: New results from the Slone Epidemiology Unit's Case Control Surveillance Study. The Royal Society of Medicine, London, September 24-26, 1991. 53. Rohan T. Hormone replacement therapy and risk of breast cancer: A populationbased case-control study in Australia. The Royal Society of Medicine, London, September 24-26, 1991. 54. Rosenberg I, Palmer JR, Shapiro S. Oestrogen replacement therapy and breast cancer: Results from the Slone Epidemiology Unit's Toronto Breast Cancer Study. The Royal Society of Medicine, London, September 24-26, 1991. 55. Ross RK, Bernstein L. Why can't we prove that HRT causes breast cancer? Methodologic and biologic challenges. The Royal Society of Medicine, London, September 24-26, 1991. 56. Weiss NS. Case-control studies of exogenous sex hormones in relation to breast cancer in women conducted in western Washington. The Royal Society of Medicine, London, September 24-26, 1991. 57. Armstrong BK. Oestrogen therapy after the menopause--boon or bane? Med J Aust 1988;148:213. 58. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991;151:67. 59. Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders D, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991;265:1985. 60. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75. 61. Gambrell RD Jr, Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol 1983;62:435. 62. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy: II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979;54:74. 63. Key TJA, Pike MC. The role of oestrogens and progestogens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 1988;24:29.
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DISCUSSION Assessing the impact of estrogen use on the risk of breast cancer is one of the more confusing issues in practice today. Many questions cannot be answered until more data emerge. Frustratingly, the few long-term studies that are now available for oral contraceptives are based on higher estrogen dosages than today's low-dose formulations. It will be another 5-10 years before conclusive data showing the effect of low-dose contraceptives on breast cancer risk are available, Dr. Speroff predicted. The studies on hormone replacement therapy that are emerging, such as the Uppsala, Sweden study, do produce waves of concern. These data must be interpreted carefully for variables that can confound the results. Dr. Judith LaRosa pointed out the hysteria being generated by lay interpretations of study results and averred that the review of studies presented today by Dr. Speroff was something from which countless audiences could benefit. Among the clinical issues raised was Dr. Dunn's question about whether women at high risk for ovarian cancer through family history ought to be prescribed low-dose oral contraceptives as a prophylaxis. Low-dose contraceptives have been shown to have a protective effect against ovarian cancer and endometrial cancer. Dr. Speroff replied that certainly when such women are in the position of needing contraception, there are enough data to recommend oral contraception emphatically. Their prophylactic use would be comparable to prescribing the pill to prevent endometriosis in patients with tubal ligations, which is frequently done. For the rare patient with a strong family history of ovarian cancer who no longer needs contraception, Dr. Speroff recommended a more drastic preventive measure---prophylactic oophorectomy. Dr. John LaRosa offered his impression that, in the aggregate, the data tend to favor a slightly increased risk of breast cancer with estrogen use. Although the difference might be so small as to not be clinically significant, and might not affect his treatment decisions with individual patients, it nonetheless appears to be there. He inquired about the rationale behind the current estrogen dose given in long-term hormone replacement therapy and asked why a lower dosage hadn't been considered. Dr. Speroff replied that there is a point at which estrogen no longer protects against bone loss. He added that the same dose may not be appropriate for everyone, and said the Food and Drug Administration is now requiring that companies seeking premarket approval for their hormone replacement product specify the lowest effective dose. The bulk of the discussion revolved around process, ie, how can policymakers, medical organizations, and individual providers behave in a responsible manner concerning these issues? Mr. Tennenbaum observed that the public seems unaware of the amount of internal scrutiny and debate going on within the medical community. He asked what the individual practitioner should be expected to do in the light of so much divided opinion, and wondered what guidance could be provided by medical specialty societies and other groups. Dr. Speroff replied that the medical societies with which he is involved-ACOG and the American Fertility Society--take that charge very seriously, and have established guidelines for practice and incorporated these topics into continuing medical education programs. Dr. Schwarz illuminated the process of consensus-building as it occurs within specialty societies. The most critical period tends to be before there are sufficient data for such groups to comfortably endorse a concept, he said--that's when mischief occurs. He said ACOG's committees tend to be conservative, that although they try to respond as quickly as possible to convincing data, they also exercise restraint against WHI Vol. 2, No. 2 S u m m e r 1992
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reaching conclusions prematurely. Meanwhile, television and the newspapers begin spreading information, and that creates pressure on such groups to respond before they're ready. Dr. Ruth Merkatz added that specialty groups have an obligation not only to inform their own members, but also to inform the public. Much of what the public learns today stems from television and lacks the perspective of professional sources who perhaps understand it best. Dr. Speroff acknowledged a "pet p e e v e ' - - t h a t the role of nurses in this area is often neglected. Nurses play a critical role in patient interactions; in this case of hormone replacement therapy, they are in a powerful position to influence patients' understanding. There was discussion about the advance release to the press of clinical data as currently practiced by some medical journals. Dr. Ravnikar pointed out that even the medical journals fall prey to wanting to get into the limelight once in a while. Dr. Speroff voiced support for a proposed Jacobs Institute conference that would focus on media reporting of women's health issues and address many of the problems raised today (ie, how to read studies properly, avoiding conclusions based on premature data, etc). Dr. John LaRosa returned to the overall issue of how broad the public message about oral contraception and hormone replacement therapy ought to be at this point. He drew a distinction between the level of certainty about these topics and that behind the issue of lowering cholesterol to prevent coronary artery disease, for example. Data for the latter are well established, and the federal government--which in his estimation is appropriately slow in acting on these matters---has endorsed a standard of care contained within the large-scale National Cholesterol Education Program. In contrast, the immaturity of data involving hormone replacement therapy would make it inappropriate to react with broadly disseminated recommendations. Dr. Speroff agreed and said for that reason he supports the efforts within the Office of Women's Health at the National Institutes of Health to design a clinical trial of hormone replacement therapy that would provide the scientific basis for developing a standard of practice. He would not await the issuance of such data in treating his own patients because, in his judgment, the evidence in favor of hormone replacement therapy already is convincing.
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