Menopause and risk of non-fatal acute myocardial infarction: an Italian case-control study and a review of the literature

Francesca Fioretti1, Alessandra Tavani1,4, Silvano Gallus1, Silvia Franceschi2 and Carlo La Vecchia1,3

1 Istituto di Ricerche Farmacologiche `Mario Negri', Via Eritrea 62, 20157 Milan, 2 Centro di Riferimento Oncologico, Via Pedemontana Occidentale, 33081 Aviano (PN) and 3 Istituto Statistica Medica e Biometria, Università degli Studi di Milano, Via Venezian 1, 20133 Milan, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The relationship between menopause and non-fatal acute myocardial infarction (AMI) was considered by analysing data from a case-control study conducted in Italy between 1983 and 1992. Cases were 429 women, below age 75 years, with a first episode of non-fatal AMI, admitted to 30 coronary care units; controls were 863 women admitted to the same network of hospitals for acute diseases other than cardiovascular, neoplastic, or hormone-related. Postmenopausal women were not at higher risk of AMI than pre/perimenopausal women, after adjustment for age and other selected covariates [multivariate odds ratio (OR) 0.99]. With reference to age at menopause, compared with women reporting menopause when <45 years, the multivariate OR were 1.54 for those aged 45–49 at menopause, 1.36 for those aged 50–52 years, and 0.97 for those aged >=53, in the absence of any trend in risk. No meaningful relationship emerged with time since menopause (OR 0.85 for <10 years since menopause). The results were similar in women aged <60 and >=60 years at AMI. Although the present study does not support a substantial relationship between menopause and non-fatal AMI, the overall epidemiological evidence is compatible with a moderate association.

Key words: acute myocardial infarction/case-control study/menopause/risk factors


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The hypothesis that menopause and consequent biological modifications are related to the risk of coronary heart disease (CHD) originally derived from the observation that incidence and mortality rates for cardiovascular disease (CVD) in women are substantially lower than in men before menopause, but tend to rise and approach those of men at older ages (Heller and Jacobs, 1978Go). In the Framingham cohort, the differences in the risk of CHD between men and women progressively diminished with each decade of age and there was a strong inverse association between age at menopause and CHD risk (Gordon et al., 1978Go; Lloyd-Jones et al., 1999Go). Most other cohort studies showed some excess CHD risk in women with earlier menopause (Colditz et al., 1987Go; Jacobsen et al., 1997Go; Cooper and Sandler, 1998Go; Cooper et al., 1999Go; Jacobsen et al., 1999Go). However, it is difficult to disentangle the simple effect of age from that of menopause on CVD, since the rise of CVD incidence and mortality may simply be due to increasing age, the two variables being strongly related. Further, the results of analytical epidemiological studies on the specific role of menopause are still open to discussion (Barrett-Connor and Bush, 1991Go; La Vecchia, 1992Go).

A protective role of female sex hormones on CHD is supported by the observation that hormonal changes related to menopause unfavourably alter the profile of some cardiovascular risk factors (La Vecchia, 1992Go; Gensini et al., 1998Go; Greendale et al., 1999Go). These include increased concentrations of cholesterol, triglycerides, low-density lipoproteins, and apolipoprotein-B, reduced levels of high-density lipoproteins and higher blood pressure (Davis et al., 1994Go; Schaefer et al., 1994Go; Dallongeville et al., 1995Go). Oestrogens have been reported to promote vasodilatation through several biological mechanisms, and to inhibit the development and progression of atherosclerosis (Mendelsohn and Karas, 1999Go). Moreover, menopausal hormone replacement therapy (HRT) has been associated with a reduction in CHD incidence and mortality in women with no previous cardiovascular events in several observational studies (Stampfer et al., 1991Go; The Writing Group for the PEPI Trial, 1995Go; Grodstein et al., 1996Go; Barrett-Connor, 1998Go). Conversely, intervention trials on women with previous CHD or at high risk of CHD show no appreciable reduction of risk (Hemminki and McPherson, 1997Go; Hulley et al., 1998Go; Petitti, 1998Go).

To further assess the potential role of menopause on the risk of non-fatal acute myocardial infarction (AMI), we considered data from a case-control study that considered hormonal factors, smoking, and other major AMI risk factors in Italian women (La Vecchia et al., 1987aGo,bGo).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The present study is based on the data of a case-control study on AMI, conducted in Italy between 1983 and 1992, whose general design has already been described (La Vecchia et al., 1987aGo,bGo, 1989Go). Originally, the study focused on oral contraceptives and other hormonal factors, and hence had an upper age limit of 54 years. This limit was raised to 74 years in 1987, and the present analysis is based on data collected until December 1992.

Cases were women with a first episode of non-fatal AMI (International Classification of Disease, ICD-9 410) defined according to the standard World Health Organization criteria (WHO, 1971), admitted to 30 coronary care units in Italy. A total of 429 patients were interviewed, aged 18–75 years (median age 52 years).

Controls were 863 women, aged 17–79 (median age 52 years), admitted to the same network of hospitals for acute diseases other than cardiovascular, neoplastic, digestive, and hormone-related conditions, or diseases associated with long-term changes in the diet. Of these, 25.3% were admitted for traumatic conditions, 36.4% had non-traumatic orthopaedic disorders (mostly low-back pain and disc disorders); 15.5% had acute surgical conditions; and 22.8% had other illnesses such as acute infections, skin, eye, ear, nose, and throat, or dental disorders. Cases and controls were not singly matched by age, but the frequency distribution by quinquennia of age was comparable. Less than 5% of cases and controls approached for interview refused.

A standard questionnaire was administered by trained interviewers during the hospital stay, including information on personal characteristics and lifestyle habits, such as education, marital status and other socio-economic indicators, smoking, alcohol and coffee drinking, anthropometric variables, diet, menstrual and reproductive factors (age at menarche, menstrual cycles, number of abortions and births, and age at and type of menopause), personal and family history of selected medical conditions, history of lifelong use of oral contraceptives (OC) and HRT. Postmenopausal women were those whose menstrual period had stopped at least 1 year before.

Data analysis
Odds ratios (OR) of AMI according to menopausal status and age at menopause, and the corresponding 95% confidence intervals (CI), were derived using unconditional multiple logistic regression, fitted by the method of maximum likelihood (Breslow and Day, 1980Go). All the regression equations included terms for study, age (quinquennia plus a continuous term, to obtain a more detailed allowance), education, smoking, body mass index (BMI), history of diabetes, hypertension and hyperlipidaemia, and use of HRT.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Table IGo gives the distribution of 429 non-fatal AMI cases and 863 control women according to age, education, body mass index, and use of HRT. Educational level was similar in AMI cases and controls. Cases were more frequently overweight (47.7% versus 41.1% of controls had a BMI >=25), and reported HRT use (mostly short-term) more often than controls. These factors were consequently allowed for in the multivariate analysis.


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Table I. Distribution of 429 cases of acute myocardial infarction (AMI) and 863 controls in women, according to age and selected covariates. Italy, 1983–1992
 
Menopausal status and other menopausal characteristics are considered in Table IIGo. The multivariate OR was 0.99 in postmenopausal compared to pre/perimenopausal women. Compared with women reporting menopause at age <45 years, the multivariate OR were 1.54 for those aged 45–49 at menopause, 1.36 for those aged 50–52 years, and 0.97 for those aged >=53, in the absence of any trend in risk (P for trend 0.997). The OR for one year of increment in age at menopause was 1.01 (95% CI 0.98–1.04). No relationship between age at menopause and risk of AMI emerged when women aged <60 and >=60 years at interview were analysed separately. With reference to time since menopause, compared to pre/perimenopausal women the OR was 0.85 for those reporting menopause <10 years earlier, and 0.52 for those whose menopause dated back >=20 years.


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Table II. Distribution of 429 cases of acute myocardial infarction (AMI) and 863 controls in women, and corresponding odds ratios with 95% confidence intervals (CI), according to menopausal characteristics. Italy, 1983–1992
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This is a hospital-based case-control study with all the inherent strengths and limitations. However, cases were women with AMI diagnosed according to strictly defined criteria (WHO, 1971), and any bias in the selection of controls should be limited because we specifically excluded any hospital admission for diseases potentially related to recognized cardiovascular risk factors. As for other potential sources of bias, participation was almost complete, cases and controls were drawn from the same catchment areas, the interviews were conducted for cases and controls during the hospital stay, and the questionnaire was tested for reproducibility (D'Avanzo et al., 1997Go). Information on status and age at menopause has been shown to be reliable and valid (Bean et al., 1979Go; Rosenberg et al., 1979Go), and separate information was collected on type of menopause to distinguish women with simple hysterectomy from those with bilateral oophorectomy (Pike et al., 1998Go). Thus, the results are not likely to be influenced by selection or information bias. Allowance for major identified potential confounding factors, including education, smoking, body mass index, selected diseases and use of HRT did not materially modify the risk estimates, and very detailed allowance was made for age (quinquennia plus a continuous term) to avoid potential underadjustment (Pike, 1987Go).

The overall epidemiological evidence on the relationship between menopause and CHD is still controversial. Most information derives from seven cohort and two case-control studies, and is summarized in Table IIIGo. As for the cohort studies, the 20-year follow-up of the Framingham Study showed a twofold increase in relative risk (RR) in post- versus premenopausal women (Kannel et al., 1976Go); in the 24-year follow-up of this cohort, based on 43 cases of fatal and non-fatal AMI, the AMI incidence rate was 1.4 in premenopausal and 3.9 in postmenopausal women (Gordon et al., 1978Go). In a cohort of Swedish women (Lapidus et al., 1985Go), based on 25 cases of AMI, the RR were 2.0 (95% CI 0.2–19.1) for women aged <=40 years at menopause, 2.2 (95% CI 0.7–7.4) and 1.4 (95% CI 0.5–3.8) for women aged <=45 and <=50 years, compared to premenopausal women. In the follow-up at 6 years of the American Nurses' Health cohort study (Colditz et al., 1987Go), compared to premenopausal women, those with natural menopause had an RR of 1.1 and those with surgical menopause had an RR of 1.7 when HRT had never been used, and respectively RR of 0.8 and 0.7 when only HRT users were included. In a study from Tromsø in Norway (Jacobsen et al., 1997Go), including 2767 cases of CHD, the RR was 0.84 (95% CI 0.65–1.08) for women aged >=53 years at menopause compared to those aged <40. In the National Health and Examination Survey (NHANES) I Study (Cooper and Sandler, 1998Go), based on 84 cases of fatal CHD, a moderate, but not significant association was observed between CHD and age at menopause, the RR being 1.50 (95% CI 0.67–3.36) for women with menopause at age <40 years compared to women with menopause at age >=50 years. In the Menstruating and Reproductive History Study (Cooper et al., 1999Go) an RR of 3.2 was found in women with natural and of 2.7 in those with surgical menopause at age <=45 years compared to women with natural menopause when aged >=51 years. At the 13-year follow-up of the California Seventh-Day Adventist Study, including 308 cases of fatal CHD (Jacobsen et al., 1999Go), increased risks of CHD were found in women with menopause either at young (35–40 years) or old age (56–60 years), the association being apparently stronger in non-HRT users.


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Table III. Relationship between coronary heart disease (CHD) and menopause in selected cohort and case-control studies
 
Two case-control studies investigated the relationship between menopause and AMI risk. An OR of 0.6 (95% CI 0.4–1.0) was found in postmenopausal women compared with premenopausal ones (Rosenberg et al., 1983Go), and an OR of 0.5 (95% CI 0.2–0.9) was found in pre- and perimenopausal women compared to postmenopausal ones (Palmer et al., 1992Go), with higher risks in women with menopause at age <45 years than in women with menopause at age >=50 years.

Thus, there is some suggestion that postmenopausal women may have a higher risk of CHD, although there is substantial heterogeneity in the results across various studies. This is not easily explained by the different types of study (cohort or case-control), the inclusion of fatal or non-fatal diseases, the inclusion of HRT users, the cut-off points selected for age at menopause and other identified factors. Some of these discrepancies may be the result of difficulties in the collection and analysis of epidemiological data on menopause. Besides uncertainties in the definition of the perimenopausal period, age at menopause is difficult to establish in women after hysterectomy and in those using HRT. Moreover, like any other time-related factor, it is important to make an extremely detailed age-adjustment for an unbiased quantification of risk (Pike, 1987Go).

Some hormonal changes at menopause might influence the risk of CVD. HRT may be protective for atherosclerosis and other cardiovascular risk factors (Writing Group for the PEPI trial, 1995; McCrohon et al., 1996Go), but may also be thrombogenic, as suggested by the short-term excess risk after starting HRT use in the Heart and Estrogen/Progestin Replacement Study (Daly et al., 1996Go; Jick et al., 1996Go; Perez Gutthann et al., 1997Go). Other potential effects include modifications of plasma lipid profile (Hulley et al., 1998Go), fibrinolysis (Petitti, 1998Go) and blood pressure (Hazzard, 1989Go); however, the potential role of such modifications on the risk of CVD is still undefined.

In conclusion, this study does not support a substantial relationship between age at menopause and non-fatal AMI; the overall epidemiological evidence is compatible with a moderate association between menopausal age and risk of CHD, also supported by the benefit reported for use of HRT in primary prevention (Petitti, 1998Go). Despite a considerable amount of research, precise epidemiological quantification of that risk is still lacking.


    Acknowledgments
 
The authors wish to thank Mrs Judy Baggott and M.Paola Bonifacino for editorial assistance. This work was conducted with the contribution of the Italian Association for Cancer Research and the Italian League against Tumours, Milan.


    Notes
 
4 To whom correspondence should be addressed Back


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Submitted on July 26, 1999; accepted on November 22, 1999.