ANNALS of Internal Medicine

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1 ANNALS of Internal Medicine AUGUST 1978 VOLUME 89 NUMBER 2 Published Monthly by the American College of Physicians Menopause and Coronary Heart Disease The Framingham Study TAVIA GORDON; WILLIAM B. KANNEL, M.D., F.A.C.P.; MARTHANA C. HJORTLAND, Ph.D.; and PATRICIA M. McNAMARA; Bethesda, Maryland; and Framingham, Massachusetts A rise in coronary heart disease incidence after menopause and a dramatic increase in the severity of the presenting disease are noted in a cohort of 2873 Framingham women who were followed up for 24 years. No premenopausal woman developed a myocardial infarction or died of coronary heart disease. Such events were common in postmenopausal women. Even in women under age 55, 40% of the postmenopausal coronary heart disease presented in these more serious forms, whether menopause was natural or surgical. The contrast was especially marked in the age group 40 to 44 years. In the age groups 45 to 49 and 50 to 54 years, incidence rates in menopausal and postmenopausal intervals were more than double those in premenopausal intervals, whether menopause was natural or surgical. In surgical menopause there was excess incidence whether the ovaries were removed or not. Postmenopausal women on hormones had a doubled risk of coronary heart disease. IN A PREVIOUS article (1) it was shown that there was a rise in the incidence of cardiovascular disease in women, and of coronary heart disease in particular, after menopause was completed. For surgical menopause in women under age 45 the increase was quite significant and statistically unequivocal. For surgical menopause in women From the Biometrics Research Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and the Framingham Heart Disease Epidemiology Study, Framingham, Massachusetts. over 45 and for natural menopause the increase appeared to be less dramatic and was short of statistical significance. These findings were based on a follow-up of women in the cohort of the Framingham Study (2). This cohort consisted of a probability sample of residents of Framingham, Massachusetts. Beginning in 1948 these 2873 women, then aged 29 through 62 years, were enrolled, given a thorough cardiovascular examination, and invited to return for routine re-examination every 2 years. The survivors are now receiving their fifteenth biennial examination. This report is based on data from the first 13 examinations. By the thirteenth examination the youngest woman in the cohort was 54 years old, and virtually all women had ceased menstruating. Since the original Framingham report on cardiovascular disease and menopause additional information has accumulated, allowing for a more detailed reanalysis of the data. It is now evident that an increase in coronary heart disease incidence is demonstrable after both surgical and natural menopause and that this increase is not restricted to younger women with premature menopause. These and other associated findings suggest that the increase in coronary heart disease incidence occurs by a sudden escalation in risk at the time of menopause. Methods At every biennial examination women were asked if they were still menstruating. If they had stopped befcause of surgical or other active intervention a careful inquiry was made as to the exact procedure used. In most instances the medical records Annals of Internal Medicine 89: , American College of Physicians 157

2 Table 1. Menopausal Women by Type of Menopause and Source of Information (Framingham Study) Type of Menopause Reported at Observed Total Examination 1 Examinations 2 to 14 < no. Natural Surgical (all) Uterus only Uterus plus Unilateral oophorectomy Bilateral oophorectomy Oophorectomy unknown Other (such as radiation) Unknown Died before menopause Lost to follow-up for menopause All forms that described the actual character of the operation were obtained. In a limited number of cases, accounting for about 13% of the information available on surgical menopause, it could be ascertained that menopause had been surgically induced, but documentation of the number of ovaries removed could not be obtained. If menstruation had ceased for natural reasons it was determined how long it had been since the last menstruation. When it was finally established that the woman had not menstruated for 12 consecutive months she was considered postmenopausal. The age assigned to the termination of menstruation was the woman's age at the completion of her last recorded menstruation. She was considered postmenopausal at the next scheduled examination. At that examination she might have been postmenopausal for as short a period as 1 month or as long as 24 months (or whatever the exact interval was since the last examination). We distinguish three categories of menstrual experience: premenopausal, menopausal, and postmenopausal. Menopausal experience is that occurring during the 2-year interval between the two consecutive examinations in which time the women clearly entered the postmenopausal state. On the average, postmenopausal experience during that interval would have lasted approximately 1 year; but, as just noted, individual women would have been postmenopausal a shorter or longer period. Premenopausal intervals are examination intervals before the menopausal interval; postmenopausal intervals are examination intervals after the menopausal interval. In all estimates of coronary heart disease incidence, women free of this disease at one examination were followed up to determine if it had developed by the next examination. Details with respect to diagnostic criteria are given elsewhere (3). Briefly, coronary heart disease was based on a history consistent with angina pectoris; a history and electrocardiographic evidence indicating coronary insufficiency; a history and electrocardiographic, enzyme, and autopsy findings indicating myocardial infarction; or death assignable to coronary heart disease. The time intervals of observation were the 2 years from one scheduled examination to the next. Multivariate analysis was done using the logistic regression, parameters of which were estimated by the method of Walker and Duncan (4). Tests of significance for incidence rates and for pooling age-specific contrasts were based on standard techniques (5, 6). Unless otherwise stated, "statistically significant" means P < Results About three fourths of the Framingham women became menopausal naturally, and about one fourth had surgical menopause, half of these involving bilateral oophorectomy (Table 1). Details of the natural history of the menopause are published elsewhere (7). Although follow-up for coronary heart disease incidence and for total mortality was essentially complete, there were 85 women for whom the age at menopause could not be determined. The coronary heart disease incidence rates for women having surgical menopause are given in Table 2. Rates for women having surgical menopause were substantially higher than for premenopausal women, the difference in the age range 40 to 54 years being statistically significant (P < 0.001). Although this experience is too limited to give very reliable estimates of relative risk, the indicated relative odds by the method of Mantel and Haenszel (6), in the age range 45 to 54 years were 2.7 to 1 (P < 0.01). The incidence rate of coronary heart disease for women who had natural menopause was also higher than that for premenopausal women (Table 3). If we contrast the postmenopausal and premenopausal experience for women aged 45 to 54 years, the odds are the same as for surgical menopause 2.7 to 1. This contrast is also statistically significant (P < 0.01). A logistic regression analysis was also done. Women free of coronary heart disease and hence still at risk of developing the disease were coded 0 when they were at the beginning of a premenopausal examination interval (as denned above) and coded 1 when they were at the beginning of a menopausal or postmenopausal interval. Table 2. Coronary Heart Disease Incidence for Women Having Surgical Menopause (Framingham Study: 24-Year Follow-up) Age and Menopausal Status * Person Coronary Heart Years Disease Cases f no. /1000/yr 40 to 44 years old Premenopausal Postmenopausal (1) (1) 4.7 Unspecified to 49 years old Premenopausal (1) 1.2 Postmenopausal (3) (1) (1) (1) 2.6 Unspecified to 54 years old Premenopausal Postmenopausal (7) (2) (4) 4.7 Unspecified (1) 2.3 * Postmenopausal status is divided according to the number of ovaries removed. The menopausal interval accounted for only a total of 564 person-years' experience (246, 236, and 82 in the respective age groups) and no coronary heart disease incidence and therefore is not shown here. t Parenthetical entries for premenopausal and postmenopausal coronary heart disease are counts of those cases presenting as coronary heart disease other than angina pectoris. Where no such cases appear there is no entry. 158 August 1978 Annals of Internal Medicine Volume 89 Number 2

3 Table 3. Coronary Heart Disease Incidence for Women Having a Natural Menopause (Framingham Study: 24-Year Follow-up) Age and Menopausal Status Person- Coronary Heart Years Disease Cases* no. /1000/yr 40 to 44 years old Premenopausal Menopausal Postmenopausal to 49 years old Premenopausal (1) 1.2 Menopausal Postmenopausal (2) to 54 years old Premenopausal Menopausal Postmenopausal (11) 4.4 * Parenthetical entries are numbers of coronary heart disease cases presenting as coronary heart disease other than angina pectoris. Only intervals at the beginning of which the woman was in the age range 40 to 54 years are considered. A bivariate regression of menopausal status (natural menopause only) and of age in years-on the incidence occurring in the next 2-year interval* was calculated. The regression coefficient for menopausal status was The relative odds calculated from this coefficient are 2.2 to 1 in the combined menopausal and postmenopausal intervals compared to premenopausal periods. These odds are only slightly less than those obtained when the data were classified in 5-year age groups, but they are short of statistical significance. If we omit the experience in women younger than 45, there is little to distinguish the coronary heart disease risk associated with surgical and natural menopause. This appearance of comparability is reinforced by a consideration of the presenting form in postmenopausal women (Table 4). Almost exactly the same proportion of cases presented as angina pectoris in both the surgical and natural series. In both series, almost exactly 30% presented as myocardial infarction. Even more striking is the contrast of postmenopausal with premenopausal experience. Of the six premenopausal cases, five presented as angina pectoris and one as coronary insufficiency. No premenopausal women developed myocardial infarction or died of coronary heart disease despite approximately 8500 premenopausal personyears' experience. If the experience of all forms of menopause in women aged 45 to 54 is combined, the odds for the combined menopausal and postmenopausal intervals are 2.4 times those of the premenopausal experience. This contrast is statistically significant (P < 0.01). The logistic analysis, where age is entered in single years, yields odds of 2.3 to 1 (P < 0.05). While emphasizing the rise in risk attendant to menopause, it is equally important to emphasize the extraordinarily low coronary heart disease incidence rates in premenopausal women of any age (8). The coronary heart disease incidence for premenopausal women aged 45 to 54 compared to that for Framingham men of the same age, is roughly 1 to 15. Moreover, most premenopausal coronary heart disease presents as angina pectoris, whereas in men under 54 only about 25% presents in that milder form. Discussion The original analysis of the Framingham experience had combined what we call here the menopausal interval with the premenopausal for comparison with postmenopausal experience. This was unreasonably conservative, substantially reducing the contrast with the postmenopausal period. In this analysis the menopausal period is kept separate, so that the low incidence of coronary heart disease in premenopausal women, as well as the remarkably low proportion of more serious manifestations, is quite clear. The separation becomes of critical importance in women aged 50 through 54 when the remaining premenopausal women are in rapid transition to the postmenopausal state. Some, but not all, of the case control studies of menopause have reported that postmenopausal women have a higher cardiovascular risk or more atherosclerosis than premenopausal women (9-15). As with most case control studies these tend to be subject to suspicion of selective bias. The Goteborg study (12), which avoided this suspicion by using a general population for control subjects, found that women with coronary heart disease were more likely to have early menopause than those in the general population. The study of Ritterband, Jaffee, and Densen (13), compared the coronary heart disease experience of women with hysterectomy and bilateral oophorectomy with that of women having only a hysterectomy. That study found no difference in coronary heart disease experience, and the researchers concluded that surgical menopause did not lead to an increased risk. The Framingham data suggest that removing either the uterus alone or removing Table 4. Incidence of Coronary Heart Disease by Presenting Evidence and Menopausal Status (Framingham Women 40 to 54: 24-Year Follow-up) Menopausal Status Presenting Evidence* Total MI CHD CI AP Death Incidence cases, no. Premenopausal Menopausal f 7 7 Postmenopausal Natural Surgical Total Hysterectomy One ovary removed Two ovaries removed Unspecified Distribution, % Postmenopausal t Natural Surgical * In order of descending priority, left to right. MI = myocardial infarction; CI = coronary insufficiency; AP = angina pectoris without other coronary heart disease manifestation; CHD = coronary heart disease. t Natural only. No coronary heart disease event reported in examination interval (2 years) in which a surgical menopause occurred. % No myocardial infarction or coronary heart disease death occurred in premenopausal or menopausal intervals. Gordon etal. Menopause and Heart Disease 159

4 Table 5. Actual and Expected Incidence of Coronary Heart Disease and Death in 6 Years According to Hormone Use in Postmenopausal Women (Framingham Study) Estrogen Women* Total Deaths Coronary Heart Use at - Disease Cases Exami- Actual Expected f nation 10 Actual Expected f < no. > For less than 1 year For more than 1 year * Alive at examination 10 and using estrogens. t Assuming age distribution of estrogen users. The specific hormone most commonly specified was Premarin. both the uterus and one or both ovaries increases the coronary heart disease risk. Although the contrasts shown by the Framingham Study seem quite substantial, particularly for the more serious manifestations of coronary heart disease, there are several questions that need answering. One question concerns the recent finding that natural menopause occurs slightly earlier in women who smoke cigarettes than in women who do not (16), a finding duplicated in the Framingham Study (7). It has been suggested that this may account for the original Framingham Study finding that menopause was associated with increased coronary heart disease risk. Because most coronary heart disease in Framingham women under age 54 occurred in the form of uncomplicated angina pectoris, and we have found no association between cigarette smoking and this manifestation, the hypothesized artifact seemed implausible. A formal multivariate analysis confirms this presumption. The logistic regression coefficient for natural menopause was when only age was controlled and was hardly changed (0.823) when the number of cigarettes smoked per day was also taken into account. An analysis restricted to coronary heart disease other than angina pectoris leads to the same conclusion. Another question concerns the speed with which coronary heart disease risk rises after menopause. This is difficult to examine prospectively, particularly given the relatively few cases available for a life table analysis. If we consider only the first five postmenopausal examination intervals, incidence rates can be construed as essentially uniform over time, whether menopause was surgical or natural. A larger body of experience might lead to a different conclusion, however. Even with a large number of cases it would be difficult, at best, to segregate an increasing incidence after menopause from an increasing incidence with age because the longer the period after menopause, the older the woman. Still, we think the most parsimonious explanation of our findings is that the impact of menopause is substantial, relatively abrupt, and augments afterwards only slowly, if at all. Other supporting evidence is obtained from the experience of postmenopausal women in the age range 55 to 74. The age at menopause for these women was, in fact, slightly greater for those in whom coronary heart disease developed during follow-up than for those in whom it did not; but the difference was not statistically significant. Not all the evidence from the Framingham Study cohort points in that direction. The relatively high coronary heart disease incidence in women in the menopausal interval would indicate that incidence rises before the complete cessation of menstruation. If risk increased only after menstruation finally stopped, the menopausal incidence should be an average of premenopausal and postmenopausal incidence, reflecting the fact that, on the average, only half the menopausal interval was a postmenopausal interval. However, the experience derived for the menopause interval itself is perhaps too meager for detailed analysis. Another question is that of the impact of prescribed postmenopausal estrogen supplement on risk of coronary heart disease. Although there have been reports of increased cancer incidence consequent to such hormone usage (17, 18), the question of association of such postmenopausal treatment with coronary heart disease is moot. Estrogen use after menopause is accompanied in our cohort by a coronary heart disease incidence about twice that observed in women not receiving such therapy, although not by an increased total mortality (Table 5). The odds of angina pectoris were particularly high (2.3 to 1) and statistically significant. Those for other forms of the disease were lower (1.6 to 1) and not statistically significant. This is consistent with a previous study that found no association between estrogen use and myocardial infarction (19). Fortunately, most of the Framingham experience reported here is from a time when estrogen therapy was relatively uncommon. Even by the tenth biennial examination only 17% of postmenopausal women aged 45 through 54 years reported that they had been using estrogen or related hormones for more than a year, and among older women use was even lower (10% at ages 55 to 64, 6% at ages 65 to 74). At previous examinations use was less. Thus, there is little evidence that postmenopausal estrogen use significantly affects our findings. In none of the seven cases in the menopausal period (natural menopause) and in only five of the 31 cases in the intervals after natural menopause was there a report of the use of estrogen supplements before the appearance of disease. The comparable figure for postmenopausal women who had surgical menopause was six of the 26. The low incidence of coronary heart disease in terms of current use of estrogen (20) is explained by the fact that the cohort first came under observation 25 years ago, before postmenopausal estrogen use became common. Current medical use of estrogen, however, will make it very difficult in the future to study the effect of menopause on coronary heart disease risk. In premenopausal women oral contraceptives apparently increase the risk of coronary heart disease (21). If estrogen treatment of postmenopausal women also increases risk, the study of the risk of the menopause per se will become exceedingly 160 August 1978 Annals of Internal Medicine Volume 89 Number 2

5 confounded. Neither oral contraceptives nor estrogen therapy is assigned at random, and because their use varies not only with socioeconomic factors but also with symptoms it will be difficult to distinguish such selective bias from pharmacologic associations. We can only speculate as to the reasons for the postmenopausal increase in coronary heart disease incidence. Natural hormonal changes occurring with menopause are exceedingly complex (22); we cannot clearly specify which, if any, lead to a rise in coronary heart disease incidence. The specification, when it is forthcoming, must account for the fact that surgical menopause without removal of the ovaries apparently leads to the same jump in risk noted with bilateral oophorectomy (plus hysterectomy). One index of these changes may be the alteration in lipid metabolism with the cessation of menstruation. This is most clearly seen by the rise of serum cholesterol levels with bilateral oophorectomy plus hysterectomy. It is also evident in natural menopause, but only if we contrast the first postmenopausal determination with that made 4 years earlier (23). These elevations in total serum cholesterol levels are apparently caused by a rise in all the lipoprotein fractions high-density, low-density and very low-density but with a decrease in the ratio of high-density to low-density lipoproteins (1). Other atherogenic factors change only trivially at the time of menopause (23). Although it is difficult to see how these lipid changes by themselves could account for the increased coronary heart disease incidence, they may supply a clue to some of the key metabolic changes that do lead both to the jump in coronary heart disease risk with menopause and the dramatic shift after menopause to the more severe manifestations of the disease. Any explanation must account, however, for the fact that when the ovaries are not removed in surgical menopause there is no discernible rise in serum cholesterol levels (23), but there is an increase in coronary heart disease risk. A careful investigation of this subject may lead to a better understanding of the factors that account for the remarkable protection against coronary heart disease enjoyed by premenopausal women. Somewhere in this tantalizing mystery may lie a lesson of profound importance in understanding the genesis and course of this disease, perhaps in men as well as women. Requests for reprints should be addressed to Tavia Gordon, Statistician; Biometrics Research Branch, National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, MD Received 17 October 1977; revision accepted 12 April References 1. KANNEL WB, HJORTLAND MC, MCNAMARA PM, GORDON T: Menopause and risk of cardiovascular disease. The Framingham Study. Ann Intern Med 85: , GORDON T, MOORE FE, SHURTLEFF D, DAWBER TR: Some methodologic problems in the long-term study of cardiovascular disease: observations on the Framingham Study. / Chronic Dis 10: , SHURTLEFF D: Some characteristics related to the incidence of cardiovascular disease and death: Framingham Study, 18-year followup, in The Framingham Study, edited by KANNEL WB, GORDON T. Washington, D.C., Department of Health, Education, and Welfare, WALKER SH, DUNCAN DB: Estimation of the probability of an event as a function of several independent variables. Biometrika 54: , FISHER RA: Statistical Methods for Research Workers, 13th ed. New York, Hafner Publishing Co., Inc., 1967, pp MANTEL N, HAENSZEL W: Statistical aspects of the analysis of data from retrospective studies of disease. / Natl Cancer Inst 22: , MCNAMARA PM, HJORTLAND MC, GORDON T, KANNEL WB: Natural history of menopause: the Framingham Study. / Cont Educ Obstet Gynecol 20:29-35, GORDON T: Coronary heart disease in young women. Incidence and epidemiology, in Proceedings of the Symposium on Coronary Heart Disease in Young Women, Edinburgh, 1977, in press 9. ROBINSON RW, HIGANO N, COHEN WD: Increased incidence of coronary heart disease in women castrated prior to the menopause. Arch Intern Med 104: , OLIVER MF, BOYD GS: Effect of bilateral ovariectomy on coronary-artery disease and serum-lipid levels. Lancet 2: , PARRISH HM, CARR CA, HALL DG, KING TM: Time interval from castration in premenopausal women to development of excessive coronary atherosclerosis. Am J Obstet Gynecol 99: , BENGTSSON C: Ischaemic heart disease in women. A study based on a randomized population sample of women and women with myocardial infarction in Goteberg, Sweden. Acta Med Scand 549 (suppl): 1-128, RITTERBAND AB, JAFFEE I A, DENSEN PM, MAGAGNA JF, REED E: Gonadal function and the development of coronary heart disease. Circulation 27: , MANCHESTER JH, HERMAN MV, GORLIN R: Premenopausal castration and documented coronary atherosclerosis. Am J Cardiol 28:33-37, NOVAK ER, WILLIAMS TJ: Autopsy comparison of cardiovascular changes in castrated and normal women. Am J Obstet Gynecol 80: , JICK H, PORTER J, MORRISON AS: Relation between smoking and age of natural menopause. Lancet 1: , ZIEL HK, FINKLE WD: Association of estrone with the development of endometrial carcinoma. Am J Obstet Gynecol 124: , MACK TM, PIKE MC, HENDERSON BE, PFEFFER RI, GERKINS VR, ARTHUR M, BROWN SE: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294: , ROSENBERG L, ARMSTRONG B, JICK H: Myocardial infarction and estrogen therapy in post-menopausal women. See reference 18, pp PFEFFER RI: Estrogen use in postmenopausal women. Am J Epidemiol 105:21-29, MANN JI, VESSEY MP, THOROGOOD M, DOLL R: Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med 72: , BAIRD DT: Patterns of sex hormone production in women. See reference HJORTLAND MC, MCNAMARA PM, KANNEL WB: Some atherogenic concomitants of menopause: the Framingham Study. Am J Epidemiol 103: , 1976 Gordon eta/. Menopause and Heart Disease 161