Menopause and Risk of Cardiovascular Disease The Framingham Study WILLIAM B. KANNEL, M.D., F.A.C.P.; MARTHANA C. HJORTLAND, Ph.D.; PATRICIA M. McNAMARA; and TAVIA GORDON; Framingham, Massachusetts; and Bethesda, Maryland

The relation of menopause to cardiovascular disease incidence was examined in women less than 55 years old from the cohort of 2873 women in the initial Framingham examination. Although the number of person-years of experience during the 20 years of observation was nearly the same for premenopausal and postmenopausal status, there were only 20 cardiovascular events among the premenopausal women in this age group whereas 70 events occurred among the postmenopausal women of the same age. In each specific age group studied incidence rates were lower in premenopausal than postmenopausal women. This was also true for coronary heart disease. Contrast for "hard" diagnoses of cardiovascular disease (excluding diagnoses of angina pectoris and intermittent claudication) was in the same direction. Although cholesterol and hemoglobin did rise somewhat more steeply in women undergoing the menopause, this greater incidence of cardiovascular disease in postmenopausal women could not be explained by the influence of the menopause on the usual cardiovascular risk factors.

WOMEN

IN AFFLUENT

SOCIETIES

have

distinctly

less

atherosclerotic cardiovascular disease, and coronary heart disease in particular, than men. A possible explanation lies in the different endocrine make-up of men and women (1-3). If this is important, comparison of the incidence of cardiovascular disease in pre- and postmenopausal women of the same age should show an even lower incidence in those women who remain premenopausal. The purpose of this report is to examine the incidence of cardiovascular disease in the Framingham cohort of women to determine if those who undergo the menopause are at greater risk of cardiovascular events than those the same age who remain premenopausal, and, if a difference is found, to examine it in light of menopause-induced changes in known cardiovascular risk factors.

vascular examination biennially since 1948. Follow-up has been quite satisfactory. Even at the 12th biennial examination 80% of the cohort still alive appeared for examination. At that time less than 3% of all women had an unknown menopausal status. Details of the study, sampling procedure, response rates, design, criteria for disease endpoints, and laboratory methods are available elsewhere (4, 5). At each biennial examination women participants were queried by the examining physician concerning their menopausal status. Women were considered to have had a natural menopause at a given examination when they reported that the menses had ceased naturally for at least 1 year before that examination and their menopause was dated as occurring at that examination. Women presenting evidence of cessation of menses resulting from surgical or other procedures were considered menopausal at the examination after the operation. All surgical menopause was confirmed by examination of surgical operative notes and pathologist's reports of the tissue removed. Of the 2873 women in the original Framingham cohort, 1752 were identified as having had a natural menopause and 752 a surgical menopause through the 10th examination. The incidence tables were constructed with data from the subset of women free of cardiovascular disease and rheumatic heart disease at Examination 1. Person-years experience for premenopausal and postmenopausal women were obtained by reclassifying this cohort of women by age, menopausal status, and disease status at each of the next nine examinations. A new event was the first appearance, in the population free of cardiovascular or rheumatic heart disease at a given examination, of cardiovascular disease or coronary heart disease in the following 2-year interval. Cardiovascular disease is defined as coronary heart disease, stroke, congestive heart failure, or intermittent claudication. Criteria for these diseases are given in previous reports (5). Age-specific probabilities were computed using the exact chisquare test, treating person-years as the number of subjects at risk. Tests for homogeneity of the age-specific relative risks follow Zelen (6). The overall probabilities summarized from the age-specific probabilities follow a method of Fisher (7). Where appropriate the method of Mantel-Haenzel was used to construct summary chi-squares to assess the differences in cardiovascular disease incidence between premenopausal and postmenopausal women and to estimate the relative risk in relation to menopausal status (8). Results SEX AND CARDIOVASCULAR DISEASE

Methods

The Framingham cohort of 5209 men and women aged 30 to 62 at entry has been offered a thorough standardized cardio• From the Framingham Heart Disease and Epidemiology Study; Framingham, Massachusetts; and the Biometrics Research Branch, National Heart and Lung Institute, National Institutes of Health; Bethesda, Maryland.

In Framingham, men develop cardiovascular disease at more than twice the rate of women (Table 1) at least in the age range younger than 60. The probability of developing a cardiovascular event by age 60 is 27.5% for men compared with 10.1% for women. Women do not achieve the coronary heart disease incidence rates of men until a

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Table 1. Incidence of Cardiovascular Disease by Age and Sex. Framingham Study: 20-Year Follow-up

Age at Examination

Rate per 1000 per Year Men

Women

3.4 2.9 5.7 9.1 16.5 25.1 27.6 26.7 37.8 53.0

0.8 0.7 1.3 3.1 6.1 10.2 18.1 22.1 26.2 50.4

yrs 29 to 34 35 to 39 40 to 44 45 to 49 50 to 54 55 to 59 60 to 64 65 to 69 70 to 74 75 to 79

decade later in life. The relative immunity of women to coronary heart disease is even greater for the more serious clinical manifestations of myocardial infarction and sudden death where women lag men in incidence rate by 20 years (5). On the other hand, the incidence rate for angina pectoris (uncomplicated) is quite comparable in the two sexes. The presenting complaint of coronary heart disease in women is predominantly angina. Men more often present with myocardial infarction and sudden death ( 9 ) . Angina in women develops de novo 85% of the time. In men it arises out of myocardial infarction more than 50% of the time. The prognosis of angina in women is more benign than in men. Atherosclerosis involving the cerebral vessels begins later in life than coronary atherosclerosis and doesn't become clinically manifest until advanced age. There is no clear male predominance for brain infarction in the Framingham data (10).

MENOPAUSE AND CARDIOVASCULAR DISEASE

To explore this possibility incidence rates for cardiovascular disease in the Framingham cohort were computed according to menopausal status and age. Women were reclassified by age and menopausal status at each examination and if still free of cardiovascular disease were considered at risk of a cardiovascular event until the next biennial examination. In the 20 years of follow-up 20 cardiovascular events occurred among premenopausal women 40 to 54 and 70 events among postmenopausal women of the same age. The reader should be cautioned by the small numbers. However, there are few prospective studies of cardiovascular disease in women and even fewer that have carefully evaluated menopausal status. Because practically all women in the Framingham Study are now postmenopausal this represents nearly all the information the study will have on premenopausal experience; hence the detailed analysis of a small amount of data. Comparison of the incidence of cardiovascular disease at specified ages showed up to age 55 a twofold cardiovascular disease incidence among postmenopausal versus premenopausal women (Table 2 ) . Numbers were too small to make accurate estimates of the impact of menopause in specific age groups. There was a suggestion, however, that menopause had a greater impact at younger ages than older. For all ages combined there is a highly significant difference in cardiovascular incidence. The twofold relative risk in postmenopausal compared with premenopausal women is highly significant (Table 2 ) . By the statistical method of Fisher it is significant at a level of 0.05. By the more sensitive method of MantelHaenszel it is significant at a level of 0.001. Incidence rates were also computed for coronary heart

SEX AND RISK FACTORS

It might be imagined that because women develop coronary disease much less frequently than men that they would have lower levels of cardiovascular risk factors. In general this is not the case. However, age-sex trends in blood lipids and blood pressure may be a factor in closing the incidence gap between the sexes with advancing age (5, 11). Although the combined effects of cholesterol and blood pressure are powerful contributors to coronary heart disease incidence in both women and men, at any level of risk factors singly and in combination, 45-year-old women have roughly half the incidence of 45-year-old men ( 5 ) . Diabetes is the only risk factor that virtually eliminates the female advantage in cardiovascular disease morbidity and mortality (5). Otherwise, the various risk factors seem to determine whether a woman will be at high or low risk within her sex but do not explain the difference in risk between the sexes. However, since the sex difference in cardiovascular disease incidence decreases with advancing age, the possibility is suggested that this change is associated with the onset of the menopause. If this is so women who have undergone the menopause would have a higher incidence of cardiovascular disease than women the same age who are still menstruating. 448

October 1976 • Annals of Internal Medicine • Volume 85 •

Table 2. Incidence of Cardiovascular Disease by Age and Menopausal Status. Framingham Study: 20-Year Follow-up

Age at Examination, Person-Years Menopausal Status at Risk

Less than 40 yrs Premenopausal Postmenopausal 40 to 44 yrs Premenopausal Postmenopausal 45 to 49 yrs Premenopausal Postmenopausal 50 to 54 yrs Premenopausal Postmenopausal Total less than 55 yrs Premenopausal Postmenopausal

NewCVD* ~~ ~ N Rate per 1000 per Year

P\

4718 454

3 1

0.6 2.2

0.308

4922 1386

3 5

0.6 3.6

0.016

4492 3792

9 15

2.0 4.0

0.105

1382 7524

5 49

3.6 6.5

0.203

15 514 13156

20 70

2.7 X 5.3

* Cardiovascular disease (CVD), is the occurrence of coronary heart disease, stroke, congestive heart failure, or intermittent claudication in women free of cardiovascular or rheumatic heart disease. t Probability that the rates for premenopausal and postmenopausal women are the same. % Adjusted to age distribution of postmenopausal women.

Number4

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Table 3. Incidence of Coronary Heart Disease by Age and Menopausal Status. Framingham Study: 20-Year Follow-up*

Age at Examination, Person-Years Menopausal Status at Risk

Less than 40 yrs Premenopausal Postmenopausal 40 to 44 yrs Premenopausal Postmenopausal 45 to 49 yrs Premenopausal Postmenopausal 50 to 54 yrs Premenopausal Postmenopausal

NewCHDf

Pt

N

Rate per 1000 per Year

4718 454

0 0

0.0 0.0

4922 1386

1 5

0.2 3.6

0.003

4492 3792

5 11

1.1 2.9

0.079

1382 7524

5 32

3.6 4.3

0.736

* Total rates not computed because the age-specific ratios differ more than would be expected by chance. t Coronary heart disease (CHD), is the occurrence of angina pectoris, myocardial infarction, coronary insufficiency, or coronary heart disease death in women free of cardiovascular or rheumatic heart disease. % Probability that the rates for premenopausal and postmenopausal women are the same.

disease. Numbers here were even smaller, with only 11 coronary events occurring among premenopausal and 48 among postmenopausal women (Table 3 ) . While agespecific estimates are unreliable, the relative risk of postmenopausal compared to premenopausal women seems to decrease with age. The relative risk at age 40 to 44 is particularly high ( P < 0 . 0 1 ) . Most menopause in this age group is surgically induced (Table 4 ) . While the relative risks at ages 45 to 49 and 50 to 54 are both greater than 1.0, neither is statistically significant at a 0.05 level. These age-specific relative risks are nonhomogenous and hence cannot properly be combined into a single average relative risk. Nevertheless, overall, the contrast between postmenopausal and premenopausal women is statistically significant at a 0.05 level. Although numbers give out when further classification by type of menopause is attempted, it appears that there is an increased risk of coronary heart disease associated with both natural and surgical menopause (Table 4 ) . For natural menopause relative risks can be calculated only for two age groups. In both of these the risk is greater for postmenopausal women than premenopausal. Because the two relative risks do not differ significantly, they can be combined by the method of Mantel-Haenszel. By this test the relative risk cannot be shown to be significantly different from 1.0. The age-specific relative risks associated with surgical menopause are all greater than 1.0. Their combined probabilities by the method of Fisher are statistically significant (P < 0.05). Because of the high correlation (0.69) between age and years postmenopausal, it is impossible to disentangle these two factors to ascertain the relation of coronary heart disease risk to number of years postmenopausal. The data suggest that women tend to lose their relative immunity to cardiovascular disease on going through the menopause. This does not show, of course, that female

reproductive physiology is the entire explanation. Comparison of cardiovascular disease rates in postmenopausal women with those in men shows that even in the postmenopausal state, women continue to exhibit a relative immunity compared to men at least through middle-age (Table 5 ) . A sizeable proportion of new cardiovascular events in women are manifest only by histories of chest or leg pain. It is conceivable that an excess of such symptoms in postmenopausal women leads to the excess cardiovascular disease incidence. To examine this possibility such diagnoses were excluded and only diagnoses of heart attack, stroke, or congestive heart failure were considered (Table 6). Although this leads to a substantial reduction in the number of new events there is no reduction in the apparent contrast, postmenopausal women having a distinctly higher incidence rate than premenopausal women. By the method of Mantel-Haenszel this is almost statistically significant at a 0.05 level for all ages combined. The development of coronary heart disease in particular and cardiovasculr disease in general was assessed among women in the Framingham cohort by age according to the number of live births reported at the initial examination. No trend was seen in the incidence of either of these disease entities in relation to fecundity. Hence this aspect of the reproductive life of women is evidently not the explanation for the relative immunity of women to cardiovascular disease. If the menopause did lead to an increase in cardiovascular disease incidence, it is not clear what the mechanism was. Weights and blood pressures did not increase at a greater rate in women who underwent the menopause than in those the same age who remained premenopausal Table 4. Incidence of Coronary Heart Disease by Age, Menopausal Status, and Type of Menopause. Framingham Study: 20-Year Follow-up*

Age at Examination, Person-Years Menopausal Status at Risk

Less than 40 yrs Premenopausal Natural menopause Surgical menopause 40 to 44 yrs Premenopausal Natural menopause Surgical menopause 45 to 49 yrs Premenopausal Natural menopause Surgical menopause 50 to 54 yrs Premenopausal Natural menopause Surgical menopause

NewCHDf ~~ ~ N Rate per 1000 per Year

P\

4718 36 406

0 0 0

0.0 0.0 0.0

4922 288 1088

1 0 5

0.2 0.0 4.6

1.000 0.001

4492 1726 2026

5 6 5

1.1 3.5 2.5

0.083 0.302

1382 4844 2618

5 21 11

3.6 4.3 4.2

1.000 1.000

* Total rates not computed because the age-specific ratios differ more than would be expected by chance. Persons with menopause other than surgical or natural are omitted from this table. t Coronary heart disease ( C H D ) , is the occurrence of angina pectoris, myocardial infarction, coronary insufficiency, or coronary heart disease death in women free of cardiovascular or rheumatic heart disease. % Probability that the rates for premenopausal and postmenopausal women of the specified type are the same. Kannel et a/. • Menopause and Cardiovascular Disease

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449

Table 5. Incidence of Cardiovascular Disease for Persons 40 to 54 Years Old by Age, Sex and Menopausal Status. Framingham Study: 20-Year Follow-up* Age at Examination

Men N

Women

Rate per Postmenopausal Premenopausal 1000 per N Rate per N Rate per Year 1000 per 1000 per Year Year

yrs 40 to 44 45 to 49 50 to 54

31 63 118

5.7 9.1 16.5

5 15 49

3.6 4.0 6.5

3 9 5

0.6 2.0 3.6

* New cardiovascular disease is the occurrence of coronary heart disease, stroke, congestive heart failure, or intermittent claudication in women free of cardiovascular or rheumatic heart disease.

(12). Cholesterol values did tend to go up moderately on undergoing the menopause, but there was no significant change in blood glucose or in vital capacity (12). Hemoglobin values rose to a greater extent with early menopause (12). These biologic concomitants of the menopause, even taken together, could explain only a small part of the increased risk women experience on undergoing the menopause. There are, of course, other risk factors that might be altered by the menopause but did not come under repeated observation at Framingham and hence cannot be assessed in this connection. Discussion

In this country cardiac mortality is the leading cause of death in both men and women, but the heart disease death rate in women is only half that in men. It is an almost universal clinical impression that coronary heart disease is more common in men than women and this is backed up by population data in affluent countries ( 1 , 3, 5, 13). At one time mortality among women during their main reproductive years exceeded that in men because of high maternal mortality. With the elimination of this problem and the improvement in social and health treatment of women with industrialization women have come to have lower mortality even during their child-bearing years. In industrialized society women have uniformly lower death rates than men. Although there is a considerable literature on the possible role of sex hormones on the genesis of cardiovascular disease (14) this possibility remains to be elucidated. Natural menopause is usually preceded by a general decrease in estrogen concentration, and the decline continues for some period after the menopause. What is more, the endocrine balance is a very complex one, and a large number of hormonal changes occur during this period. It has been noted that lipids, which have been found to play an important role in the development of clinical atherosclerotic disease (11), may be altered by the administration of estrogen, and that the partition of cholesterol in the alpha and beta lipoproteins differs in the two sexes (15-17). Both before and after the menopause, alpha lipoprotein cholesterol (which appears to be 450

"protective" against coronary heart disease) is higher in women than men, but if anything, more so after menopause than before. Concurrently, however, cholesterol in the beta fraction for women rises even more rapidly, while remaining essentially unchanged for men older than that age range. Cholesterol in the prebeta lipoprotein declines with age in men but rises in women (18). By inference the increase in total blood cholesterol in women at menopause must be primarily accounted for by a rise in the beta lipoprotein fraction. To check this out, mean levels of total cholesterol, and the alpha, beta, and prebeta fractions were assessed at Examination 2 in pre- and postmenopausal women aged 40 to 49 (Table 7 ) . The findings showed that the increase in total cholesterol is indeed largely in the beta fraction. However, there is also a rise in the prebeta fraction and of the two the rise in the prebeta fraction is proportionally the greater. There was no discernible change in the alpha fraction with menopause. The Framingham data clearly suggest that the greater cardiovascular disease incidence in postmenopausal women is more strongly manifest at younger ages than older. This is consistent with an hormonal explanation because it is well known that estrogen levels decrease gradually as the age of natural menopause approaches. Thus the contrast in hormonal status between women who are still menstruating and those who are not will be greater, on the average, at younger ages than older. Although a number of case-control studies have reported that postmenopausal women have a higher cardiovascular risk or more atherosclerosis than premenopausal women of the same age (19-22) not all studies report a difference (23-25). However, except for the Goteborg study, which uses a general population sample for controls, these various studies all raise questions of selective bias that are difficult to resolve. Table 6. Incidence of Hard Cardiovascular 1Disease by Age and Menopausal Status. Framingham Study: 20-Year Follow-up Age at Examination, Menopausal Status

Less thai. 40 yrs Premenopausal Postmenopausal 40 to 44 yrs Premenopausal Postmenopausal 45 to 49 yrs Premenopausal Postmenopausal 50 to 54 yrs Premenopausal Postmenopausal Total less than 55 yrs Premenopausal Postmenopausal

Person-Years at Risk

New Hard CVD* N

*t

Rate per 1000 per Year

4718 454

2 0

0.4 0.0

4922 1386

1 1

0.2 0.7

4492 3792

4 8

0.9 2.1

0.160

1382 7524

2 30

1.4 4.0

0.147

15 514 13 156

9 39

3.0

1.000

Lit

* Hard cardiovascular disease (CVD), is the occurrence of coronary heart disease other than angina pectoris, stroke, or congestive ]tie art failure in women free of cardiovascular or ;rheumatic heart disease t Probability that the rates for premenopausal and postmenopausal women are the same. t Adjusted to age distribution of postmenopausal women.

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Table 7. Aged-Adjusted Mean Levels of Total Cholesterol and Cholesterol in Alpha, Beta, and Prebeta Lipoproteins. Women Aged 40 to 49 by Menopausal Status: Framingham Study, Examination 2 Premenopausal*

Postmenopausal

Mean, mg/dl Number Alpha t Betaf Prebeta f Total cholesterol

499 56.41 144.67 18.97 220.04

296 57.70 157.11 22.46 237.28

* Premenopausal classification excludes 57 women who were premenopausal at the examination of lipid determination but underwent a natural menopause between that examination and the next examination, that is, within 2-years. t Estimated from lipoprotein quantifications at Examination 2.

Routine vital statistics provide no support to the thesis that the menopause leads to a jump in cardiovascular risk because the reported cardiovascular disease death rates rise steadily and with no acceleration through the menopausal age span. On the other hand vital statistics do not distinguish between deaths associated with new and those associated with old cardiovascular events. A new cardiovascular event occurring before the menopause may result in a death after the menopause. A new cardiovascular event occurring shortly after the menopause may never lead to death or may lead to death many years later. Hence it can hardly be argued that routine vital statistics are inconsistent with the Framingham data. This is reinforced by the observation that only eight of the 70 new cardiovascular events after menopause that form the basis for this report were immediately fatal, as were only two of the 20 cardiovascular events arising in the premenopausal control population. Although mortality data from the general population cannot be argued to be inconsistent with the findings of this study, it may seem paradoxical that there is no very marked steepening of the curve for cardiovascular disease incidence by age (Table 1) through the span covering the onset of menopause, despite the fact that postmenopausal women have three times the cardiovascular disease incidence of premenopausal women. The explanation for this lies in the gradual increase with age in the proportion of women postmenopausal. It should also be noted that the data as presented slightly overstate the contrast in incidence between premenopausal and postmenopausal women. Despite the fact that incidence is calculated by 5-year age groups it is nonetheless true that even within these age groups the postmenopausal women are slightly older on the average than premenopausal: on the average 0.6 years older, both in the population at risk and (in those age groups with sufficient numbers) in the cases of cardiovascular disease that appeared. Myocardial infarction in young menstruating women is decidedly rare and occurs at only a fraction of the rate of men the same age. When it occurs hypertension, diabetes, and hyperlipidemia are usually found to account for it (22, 27, 28). The data at Framingham tend to support the hypothesis that women in their reproductive stage of life are protected from atherosclerotic cardiovascular disease

and that this is lost on undergoing the menopause. The jump in cardiovascular disease incidence at menopause could not be explained by the changes recorded in any of the usual risk factors, singly or in combination. Hence some other feature of the menopause must account for this increase in risk, a feature still to be firmly determined. ACKNOWLEDGMENTS: Received 1 March 1976; revision accepted 7 July 1976. • Requests for reprints should be addressed to Marthana C. Hjortland, Ph.D.; Biometrics Research Branch, National Heart and Lung Institute, National Institutes of Health; Bethesda, MD 20014. References 1. MASTER AM, DACK S, JAFFEE HL: Age, sex and hypertension in

myocardial infarction due to coronary occlusion. Arch Intern Med 64:767-786, 1939 2. LEVY H, ROAS EP: Coronary artery disease in women. JAMA 107:97-102, 1936 3. OLIVER MF, BOYD GS: Coronary atherogenesis—an endocrine

problem? Minn Med 38:794-799, 1955 4. GORDON T, MOORE FE, SHURTLEFF D, DAWBER TR:

Some

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analysis of categorical tables by linear models. J Biomed Syst 2:3-48, 1971 7. FISHER RA: Statistical Methods for Research Workers, 13th ed. New York, Haffner, 99-100, 1967 8. MANTEL N, HAENSZEL W: Statistical aspects of the analysis of

data from retrospective studies of disease. J Natl Cancer Inst 22:719-745, 1959 9. KANNEL WB, FEINLEIB M: Natural history of angina pectoris in the Framingham study. Am J Cardiol 29:154-163, 1972 10. KANNEL WB: Current status of epidemiology of brain infarction associated with occlusive arterial disease. Stroke 2:295-317, 1971 11. KANNEL WB, GARCIA MJ, MCNAMARA PM, et al: Serum lipid

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October 1976 • Annals of Internal Medicine • Volume 85 • Number 4

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Menopause and risk of cardiovascular disease: the Framingham study.

Menopause and Risk of Cardiovascular Disease The Framingham Study WILLIAM B. KANNEL, M.D., F.A.C.P.; MARTHANA C. HJORTLAND, Ph.D.; PATRICIA M. McNAMAR...
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