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
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Abstract |
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Key words: acute myocardial infarction/case-control study/menopause/risk factors
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Introduction |
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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, 1992; Gensini et al., 1998
; Greendale et al., 1999
). 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., 1994
; Schaefer et al., 1994
; Dallongeville et al., 1995
). Oestrogens have been reported to promote vasodilatation through several biological mechanisms, and to inhibit the development and progression of atherosclerosis (Mendelsohn and Karas, 1999
). 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., 1991
; The Writing Group for the PEPI Trial, 1995
; Grodstein et al., 1996
; Barrett-Connor, 1998
). Conversely, intervention trials on women with previous CHD or at high risk of CHD show no appreciable reduction of risk (Hemminki and McPherson, 1997
; Hulley et al., 1998
; Petitti, 1998
).
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., 1987a,b
).
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Materials and methods |
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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 1875 years (median age 52 years).
Controls were 863 women, aged 1779 (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, 1980). 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.
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Results |
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Discussion |
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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 III. 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., 1976
); 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., 1978
). In a cohort of Swedish women (Lapidus et al., 1985
), based on 25 cases of AMI, the RR were 2.0 (95% CI 0.219.1) for women aged
40 years at menopause, 2.2 (95% CI 0.77.4) and 1.4 (95% CI 0.53.8) 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., 1987
), 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., 1997
), including 2767 cases of CHD, the RR was 0.84 (95% CI 0.651.08) 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, 1998
), 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 0.673.36) 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., 1999
) 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., 1999
), increased risks of CHD were found in women with menopause either at young (3540 years) or old age (5660 years), the association being apparently stronger in non-HRT users.
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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, 1987).
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., 1996), 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., 1996
; Jick et al., 1996
; Perez Gutthann et al., 1997
). Other potential effects include modifications of plasma lipid profile (Hulley et al., 1998
), fibrinolysis (Petitti, 1998
) and blood pressure (Hazzard, 1989
); 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, 1998). Despite a considerable amount of research, precise epidemiological quantification of that risk is still lacking.
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Acknowledgments |
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Notes |
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References |
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Submitted on July 26, 1999; accepted on November 22, 1999.